Fused tricyclic ring derivatives as src homology-2 phosphate inhibitors

ABSTRACT

The present disclosure provides certain fused tricyclic ring derivatives that are Src Homology-2 phosphatase (SHP2) inhibitors and are therefore useful for the treatment of diseases treatable by inhibition of SHP2. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.17/025,790, filed Sep. 18, 2020, which is a continuation of U.S.application Ser. No. 15/930,309, filed May 12, 2020, now U.S. Pat. No.10,894,797, issued Jan. 19, 2021, which is a continuation of U.S.application Ser. No. 16/573,900, filed Sep. 17, 2019, now abandonedwhich in turn claims the benefit of U.S. Provisional Application No.62/733,061 filed Sep. 18, 2018, U.S. Provisional Application No.62/749,655 filed Oct. 23, 2018, U.S. Provisional Application No.62/810,911 filed Feb. 26, 2019, U.S. Provisional Application No.62/883,120 filed Aug. 6, 2019, and U.S. Provisional Application No.62/883,121 filed Aug. 6, 2019; the entireties of which are hereinincorporated by reference.

FIELD OF THE DISCLOSURE

The present disclosure provides certain fused tricyclic ring derivativesthat are Src Homology-2 phosphatase (SHP2) inhibitors and are thereforeuseful for the treatment of diseases treatable by inhibition of SHP2.Also provided are pharmaceutical compositions containing such compoundsand processes for preparing such compounds.

BACKGROUND

SHP2 is a non-receptor protein phosphatase ubiquitously expressed invarious tissues and cell types (see reviews: Tajan M et al., Eur J MedGenet 2016 58(10):509-25; Grossmann K S et al., Adv Cancer Res 2010106:53-89). SHP2 is composed of two Src homology 2 (N-SH2 and C-SH2)domains in its NH2-terminus, a catalytic PTP (protein-tyrosinephosphatase) domain, and a C-terminal tail with regulatory properties.At the basal state, the intermolecular interactions between the SH2domains and the PTP domain prevent the access of substrates to thecatalytic pocket, keeping SHP2 into a closed, auto-inhibitedconformation. In response to stimulation, SHP2 activating proteinsbearing phosphor-tyrosine motifs bind to the SH2 domains, leading toexposure of active site and enzymatic activation of SHP2.

SHP2 plays important roles in fundamental cellular functions includingproliferation, differentiation, cell cycle maintenance and motility. Bydephosphorylating its associated signaling molecules, SHP2 regulatesmultiple intracellular signaling pathways in response to a wide range ofgrowth factors, cytokines, and hormones. Cell signaling processes inwhich SHP2 participates include the RAS-MAPK (mitogen-activated proteinkinase), the PI3K (phosphoinositol 3-kinase)-AKT, and the JAK-STATpathways.

The RAS-MAPK signaling pathway is crucial for tumor formation andmaintenance. Genes encoding various components of this pathway,including RTKs (receptor tyrosine kinases), SHP2, NF1, RAS, or RAF aremutated in cancers, leading to upregulation of MAPK signaling. SHP2 alsoplays a signal-enhancing role on this pathway, acting downstream of RTKsand upstream of RAS. RTK-driven cancer cells were demonstrated to dependon SHP2 for survival. Thus, SHP2 inhibitor has been proposed as a validtreatment for RTK-driven cancers (see Prahallad, A. et al. Cell Reports12, 1978-1985 (2015); Chen Y N, Nature 535, 148-152(2016)).

A lot of efforts have been made to develop pharmacological agentstargeting various nodes along the RAS-MAPK pathway, such as RTKinhibitors, BRAF inhibitors, and MEK inhibitors for the treatment ofcancer. Although these agents demonstrate good initial efficacy,resistance occurs frequently to these agents. One common mechanism ofresistance involves activation of RTKs that fuel reactivation of theMAPK signaling. Since SHP2 is required downstream of multiple RTKs forsignal transduction, SHP2 inhibition may provide a general strategy forpreventing resistance to MAPK pathway targeted cancer drugs. Recentstudies in preclinical models have shown that SHP2 inhibition overcomesresistance and offers synergistic therapeutic effects when combined withan ALK inhibitor (see Dardaei L et al. Nat Med. 24, 512-17 (2018)), MEKinhibitor (see Mainardi, S. et al. Nat. Med.https://doi.org/10.1038/s41591-018-0023-9 (2018); Ruess, D. A. et al.Nat. Med. https://doi.org/10.1038/s41591-018-0024-8 (2018); Wong, G. S.et al. Nat. Med. https://doi.org/10.1038/s41591018-0022-x (2018); FedeleC et al. Cancer Discov pii: CD-18-0444. doi:10.1158/2159-8290.CD-18-0444 (2018)), or BRAF inhibitor (see Prahallad,A. et al. Cell Reports 12, 1978-1985 (2015)). Especially, the combinedinhibition of MEK/SHP2 has been identified to have potential to treatcancers driven by KRAS, the most frequently mutated oncogene. Despiteyears of efforts, inhibitors directly targeting KRAS has not yet beensuccessfully developed for clinical use. Inhibiting MEK, the downstreameffector of KRAS, only transiently suppressed MAPK signaling. Thediscovery of MEK/SHP2 dual inhibition makes important strides in thelong-time effort to better understand and to therapeutically targetKRAS-driven cancers.

Given the essential physiological functions SHP2 plays, targetingderegulation of SHP2 is expected to have broad therapeutic applications.Gain of function mutations in PTPN11, the gene that encodes SHP2, havebeen causally linked to several human diseases, including NoonanSyndrome, juvenile myelomonocytic leukemias, acute myeloid leukemia,myelodysplastic syndrome, and acute B lymphoblastic lymphoblasticleukemia. SHP2 functions as an oncogene, and its overexpression and/oractivating mutations are reported in various solid tumors, such asneuroblastoma, breast cancer, colon cancer, lung cancer, melanoma, andhepatocellular carcinoma.

Furthermore, SHP-2 is believed to mediate inhibitory immune checkpointsignaling of multiple receptors (e.g. PD-1) by dephosphorylating CD28.To support this notion, a dominant negative SHP-2 abrogates PD-1signaling pathways and restores function of cytotoxic CAR T cells.Therefore, SHP-2 inhibitors have potential for use in combinationtherapy with existing targeted and Immune-Oncology (IO) agents.

In addition to human tumors, increases in expression or activity of SHP2have been implicated in the pathogenesis of autoimmune diseases such assystemic lupus erythematosus (Wang J et al. J Clin Invest. 2016 Jun. 1;126(6):2077-92) and rheumatoid arthritis (see Stanford S. M et al.Arthritis Rheum. 2013 May; 65(5):1171-80; Maeshima K et al. JCI Insight.2016 May 19; 1(7)). Recently, SHP2 has also been characterized as amolecular checkpoint for TGFβ-induced JAK2/STAT3 signaling, suggestingthat SHP2 inhibition may offer therapeutic benefit for the treatment offibrosis (see Zehender A et al. Nat Commun. 2018 Aug. 14; 9(1):3259).Accordingly, SHP2 represents a highly attractive target for thedevelopment of novel therapies to treat various diseases.

SUMMARY

In a first aspect, provided is a compound of Formula (I):

wherein:

A and E are independently selected from a bond, CH₂, O, NH, S, andS(O)₂;

Z is hydrogen, alkyl, halo, haloalkyl, haloalkoxy, cyano, cycloalkyl,heterocyclyl, heteroaryl (wherein cycloalkyl, heterocyclyl, andheteroaryl are optionally substituted with one to three halo),—O(alk)_(y)R^(a), —O(alk)OR^(b), —S(O)R^(c), —S(O)₂R^(d),—NR^(e)C(O)R^(f), —NR^(g)SO₂R^(h), —OC(O)NR^(i)R^(j), —C(O)NR¹R^(m),—S(O)₂NR^(n)R^(o), —NR^(p)R^(q), —NR^(r)C(O)C(O)R^(s) or -Y-M (wherein Yis bond, O, or SO₂ and M is alkyl, haloalkyl, cycloalkyl, heterocyclyl,or heteroaryl wherein alkyl, haloalkyl, cycloalkyl, heterocyclyl andheteroaryl are substituted with —O(alk)_(y)R^(a), —O(alk)OR^(b),—S(O)R^(c), —S(O)₂R^(d), —NR^(e)C(O)R^(f), —NR^(g)SO₂R^(h),—OC(O)NR^(i)R^(j), —C(O)NR^(k)R^(m), —S(O)₂NR^(n)R^(o), —NR^(p)R^(q), or—NR^(r)C(O)C(O)R^(s) and cycloalkyl, heterocyclyl, and heteroaryl areoptionally further substituted with 1 to 3 halo); wherein each y is 0 or1, each alk is alkylene, and each R^(c), R^(d), R^(f), R^(h), and R^(s)are independently alkyl, cycloalkyl, cycloalkylalkyl, optionallysubstituted heterocyclyl, optionally substituted heterocyclylalkyl,optionally substituted aryl, optionally substituted aralkyl, optionallysubstituted heteroaryl, or optionally substituted heteroaralkyl; andeach R^(a), R^(b), R^(e), R^(g), R^(i), R^(j), R^(k), R^(m), R^(n),R^(o), R^(p), R^(q), R^(r), and R^(s) are independently hydrogen, alkyl,cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted heteroaryl, or optionally substitutedheteroaralkyl; or, independently of each other, each R^(i) and R^(j),R^(k) and R^(m), R^(n) and R^(o), and R^(p) and R^(q), together with thenitrogen atom to which they are attached form optionally substitutedheterocyclyl;

R¹, R², R³, and R⁴ are independently selected from hydrogen, alkyl,cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, cyano, hydroxy,hydroxylalkyl, amino, and aminoalkyl;

or one of R¹ and R², and R³ and R⁴, when attached to the same carbon,combine to form oxo, alkyldienyl, 3 to 6 membered cycloalkylene, or 4 to6 membered optionally substituted heterocyclylene;

R⁵ and R⁶ are independently selected from hydrogen, alkyl, cycloalkyl,halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, cyano, hydroxylalkyl,amino, and aminoalkyl, or one of R⁵ and R⁶ is optionally substitutedheterocyclyl and the other of R⁵ and R⁶ is selected from hydrogen,alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, cyano,hydroxylalkyl, amino, and aminoalkyl;

L is bond, O, S, S(O), S(O)₂, or CR⁷R⁸ where R⁷ and R⁸ are independentlyhydrogen or alkyl;

Z¹ is a group of formula (a) or (b):

wherein:

R⁹ is hydrogen, alkyl, halo, hydroxy, amino, or haloalkyl;

R¹⁰ is hydrogen, alkyl, halo, hydroxy, hydroxyalkyl, —CD₂OH,alkylsulfoxide, alkylsulfonyl, amino, aminoalkyl, aminosulfonyl,aminocarbonyl, carboxy, cyano, or alkoxycarbonyl;

R¹³ is hydrogen, alkyl, halo, hydroxy, amino, or haloalkyl;

R¹⁴ is hydrogen, alkyl, or haloalkyl;

R¹¹ and R¹⁵ are selected from amino and aminoalkyl;

R¹² and R¹⁶ are selected from hydrogen, cyano, halo, alkyl, haloalkyl,alkoxy, haloalkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl,where alkyl, cycloalkyl, aryl, heterocyclyl and heteroaryl areoptionally substituted with one to three substituents independentlyselected from alkyl, halo, haloalkyl, haloalkoxy, alkoxy, and cyano;

or R¹¹ and R¹², and R¹⁵ and R¹⁶ together with the carbon atom to whichthey are attached form a ring of formula (c):

wherein:

e is 0, 1, or 2;

k is 0, 1, or 2 provided e+k is 1, 2, or 3;

q is 0, 1, or 2, or 3;

R¹⁷ and R¹⁸ are independently selected from hydrogen, alkyl, cycloalkyl,and haloalkyl;

each R¹⁹ is independently selected from hydrogen, alkyl, halo,haloalkyl, haloalkoxy, alkoxy, hydroxy, cyano, alkylsulfoxide,alkysulfonyl, oxo, cycloalkyl, optionally substituted heterocyclyl, andoptionally substituted heteroaryl; or

when two R¹⁹ groups are attached to the same carbon atom, the two R¹⁹groups together with the carbon atom to which they are attached formcycloalkylene or heterocyclylene.

ring D is absent or present; wherein:

-   -   (i) when ring D is absent, then one of Q and W is CH₂, O, S,        S(O), S(O)₂, or NH; and the other of Q and W is CH₂; and    -   (ii) when ring D is present, then Q and W are independently N or        C provided only one of Q and W is N; and ring D is phenyl or a 5        or 6 membered heteroaryl ring which, including Q and W, contains        one to three heteroatoms independently selected from N, O, and S        and ring D is optionally substituted with one or two        substituents independently selected from alkyl, cycloalkyl,        halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl,        cyano, amino, aminoalkyl, carboxy, and optionally substituted        heterocyclyl;        or a pharmaceutically acceptable salt thereof.

In a second aspect, provided is a compound of Formula (IA):

wherein:

A and E are independently selected from a bond, CH₂, O, NH, S, andS(O)₂;

Z is hydrogen, alkyl, halo, haloalkyl, haloalkoxy, cyano, cycloalkyl,heterocyclyl, heteroaryl (wherein cycloalkyl, heterocyclyl, andheteroaryl are optionally substituted with one to three halo),—O(alk)_(y)R^(a), —O(alk)OR^(b), —S(O)R^(c), —S(O)₂R^(d),—NR^(e)C(O)R^(f), —NR^(g)SO₂R^(h), —OC(O)NR^(i)R^(j), —C(O)NR^(k)R^(m),—S(O)₂NR^(n)R^(o), —NR^(p)R^(q), —NR^(r)C(O)C(O)R^(s) or -Y-M (wherein Yis bond, O, or SO₂ and M is alkyl, haloalkyl, cycloalkyl, heterocyclyl,or heteroaryl wherein alkyl, haloalkyl, cycloalkyl, heterocyclyl andheteroaryl are substituted with —O(alk)_(y)R^(a), —O(alk)OR^(b),—S(O)R^(c), —S(O)₂R^(d), —NR^(e)C(O)R^(f), —NR^(g)SO₂R^(h),—OC(O)NR^(i)R^(j), —C(O)NR^(k)R^(m), —S(O)₂NR^(n)R^(o), —NR^(p)R^(q), or—NR^(r)C(O)C(O)R^(s) and cycloalkyl, heterocyclyl, and heteroaryl areoptionally further substituted with 1 to 3 halo); wherein each y is 0 or1, each alk is alkylene, and each R^(c), R^(d), R^(f), R^(h), and R^(s)are independently alkyl, cycloalkyl, cycloalkylalkyl, optionallysubstituted heterocyclyl, optionally substituted heterocyclylalkyl,optionally substituted aryl, optionally substituted aralkyl, optionallysubstituted heteroaryl, or optionally substituted heteroaralkyl; andeach R^(a), R^(b), R^(e), R^(g), R^(i), R^(j), R^(k), R^(m), R^(n),R^(o), R^(p), R^(q), R^(r), and R^(s) are independently hydrogen, alkyl,cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted heteroaryl, or optionally substitutedheteroaralkyl; or, independently of each other, each R^(i) and R^(j),R^(k) and R_(m), R^(n) and R^(o), and R^(p) and R^(q), together with thenitrogen atom to which they are attached form optionally substitutedheterocyclyl;

R¹, R², R³, and R⁴ are independently selected from hydrogen, alkyl,cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, cyano, hydroxy,hydroxylalkyl, amino, and aminoalkyl;

or one of R¹ and R², and R³ and R⁴, when attached to the same carbon,combine to form oxo, alkyldienyl, 3 to 6 membered cycloalkylene, or 4 to6 membered optionally substituted heterocyclylene;

R⁵ and R⁶ are independently selected from hydrogen, alkyl, cycloalkyl,halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, cyano, hydroxylalkyl,amino, and aminoalkyl, or wherein one of R³ and R⁶ is optionallysubstituted heterocyclyl and the other of R⁵ and R⁶ is selected fromhydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy,hydroxy, cyano, hydroxylalkyl, amino, and aminoalkyl;

L is bond, O, S, S(O), S(O)₂, or CR⁷R⁸ where R⁷ and R⁸ are independentlyhydrogen or alkyl;

Z¹ is a group of formula (a) or (b):

wherein:

R⁹ is hydrogen, alkyl, halo, hydroxy, amino, or haloalkyl;

R¹⁰ is hydrogen, alkyl, halo, hydroxy, hydroxyalkyl, —CD₂OH,alkylsulfoxide, alkylsulfonyl, amino, aminoalkyl, aminosulfonyl,aminocarbonyl, carboxy, cyano, or alkoxycarbonyl;

R¹³ is hydrogen, alkyl, halo, hydroxy, amino, or haloalkyl;

R¹⁴ is hydrogen, alkyl, or haloalkyl;

R¹¹ and R¹⁵ are selected from amino and aminoalkyl;

R¹² and R¹⁶ are selected from hydrogen, cyano, halo, alkyl, haloalkyl,alkoxy, haloalkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl,where alkyl, cycloalkyl, aryl, heterocyclyl and heteroaryl areoptionally substituted with one to three substituents independentlyselected from alkyl, halo, haloalkyl, haloalkoxy, alkoxy, and cyano;

-   -   or R¹¹ and R¹², and R¹⁵ and R¹⁶ together with the carbon atom to        which they are attached form a ring of formula (c):

wherein:

e is 0, 1, or 2;

k is 0, 1, or 2 provided e+k is 1, 2, or 3;

q is 0, 1, or 2, or 3;

R¹⁷ and R¹⁸ are independently selected from hydrogen, alkyl, cycloalkyland haloalkyl,

each R¹⁹ is independently selected from hydrogen, alkyl, halo,haloalkyl, haloalkoxy, alkoxy, hydroxy, cyano, alkylsulfoxide,alkylsulfonyl, oxo, cycloalkyl, optionally substituted heterocyclyl, andoptionally substituted heteroaryl; or

when two R¹⁹ groups are attached to the same carbon atom, the two R¹⁹groups together with the carbon atom to which they are attached formcycloalkylene or heterocyclylene.

ring D is absent or present; wherein:

-   -   (i) when ring D is absent, then one of Q and W is CH₂, O, S,        S(O), S(O)₂, or NH; and the other of Q and W is CH₂; and    -   (ii) when ring D is present, then Q and W are independently N or        C provided only one of Q and W is N; and ring D is phenyl or a 5        or 6 membered heteroaryl ring which, including Q and W, contains        one to three heteroatoms independently selected from N, O, and S        and ring D is optionally substituted with one or two        substituents independently selected from alkyl, cycloalkyl,        halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl,        cyano, amino, aminoalkyl, carboxy, and optionally substituted        heterocyclyl;

or a pharmaceutically acceptable salt thereof; provided that when thecompound of Formula (I), or a pharmaceutically acceptable salt thereof,is a compound of formula

or a pharmaceutically acceptable salt thereof, where R⁹ is hydrogen, R¹⁰is other than hydrogen, amino, and aminoalkyl, and L, R¹¹ and R¹² are asdefined in Formula (I); then:

(i) when four of R¹, R², R³, R⁴, R⁵, and R⁶ are hydrogen and remainingtwo of R¹, R², R³, R⁴, R⁵, and R⁶, are independently selected fromhydrogen, alkyl, cycloalkyl, amino, halo, haloalkyl, alkoxy, haloalkoxy,hydroxy, hydroxyalkyl, cyano, and aminoalkyl; then Z is other thanhydrogen, alkyl, halo, haloalkyl, haloalkoxy, cyano, —OR^(a) (whereR^(a) is hydrogen or alkyl), —OC(O)NH₂, —O-tetrahydrofuran-3-yl,—O-oxetan-3-yl, cyano, pyrazol-1-yl, —CH₂OCH₃, —OCH₂OCH₃,—OCH₂cyclopropyl, —O—CH₂CH₂OCH₃, and —SO₂CH₃,

(ii) when R⁵ and R⁶ are hydrogen and two of R¹, R², R³, and R⁴ arehydrogen, and one of a) R¹ and R² and b) R³ and R⁴, are hydrogen and theother of a) R¹ and R², and b) R³ and R⁴ are attached to the same carbonand are combined together to form alkylidene, 3 to 6 memberedcycloalkylene or 4 to 6 membered heterocyclylene, then Z is other thanhydrogen, alkyl, halo, haloalkyl, haloalkoxy, cyano, cycloalkyl, —OR^(a)(where R^(a) is hydrogen or alkyl), —NH₂, and -Y-M (wherein Y is bondand M is alkyl substituted with —OR^(a) or —NR^(p)R^(q) wherein eachR^(q) is hydrogen or alkyl and R^(p) and R^(q) are independentlyhydrogen, alkyl, hydroxyalkyl or alkoxyalkyl or R^(p) and R^(q) togetherwith the nitrogen atom to which they are attached form optionallysubstituted heterocyclyl); and

(iii) when Z is hydrogen, one of a) R¹ and R², and b) R³ and R⁴ areattached to the same carbon and are combined together to form 3 to 6membered cycloalkylene or 4 to 6 membered heterocyclylene, and three ofthe remaining R¹, R², R³, R⁴, R⁵, and R⁶ are hydrogen, then theremaining one of R¹, R², R³, R⁴, R⁵, and R⁶ is not hydrogen, alkyl,cycloalkyl, halo, haloalkyl, cyano, hydroxy, alkoxy, haloalkoxy,hydroxyalkyl, aminoalkyl, or amino.

In a third aspect provided is a compound of Formula (IB):

A and E are independently selected from a bond, CH₂, O, NH, S, andS(O)₂;

Z is hydrogen, alkyl, haloalkyl, cyano, cycloalkyl, heterocyclyl,heteroaryl (wherein cycloalkyl, heterocyclyl, and heteroaryl areoptionally substituted with one to three halo), —O(alk)_(y)R^(a),—O(alk)OR^(b), —S(O)R^(c), —S(O)₂R^(d), —NR^(e)C(O)R^(f),—NR^(g)SO₂R^(h), —OC(O)NR^(k)R^(m), —C(O)NR^(k)R^(m), —S(O)₂NR^(n)R^(o),—NR^(p)R^(q), —NR^(r)C(O)C(O)R^(s) or -Y-M (wherein Y is bond, O, or SO₂and M is alkyl, haloalkyl, cycloalkyl, heterocyclyl, or heteroarylwherein alkyl, haloalkyl, cycloalkyl, heterocyclyl and heteroaryl aresubstituted with —O(alk)_(y)R^(a), —O(alk)OR^(b), —S(O)R^(c),—S(O)₂R^(d), —NR^(e)C(O)R^(f), —NR^(g)SO₂R^(h), —OC(O)NR^(i)R^(j),—C(O)NR^(k)R^(m), —S(O)₂NR^(n)R^(o), —NR^(p)R^(q), or—NR^(r)C(O)C(O)R^(s) and cycloalkyl, heterocyclyl, and heteroaryl areoptionally further substituted with 1 to 3 halo); wherein each y is 0 or1, each alk is alkylene, and each R^(c), R^(d), R^(f), R^(h), and R^(s)are independently alkyl, cycloalkyl, cycloalkylalkyl, optionallysubstituted heterocyclyl, optionally substituted heterocyclylalkyl,optionally substituted aryl, optionally substituted aralkyl, optionallysubstituted heteroaryl, or optionally substituted heteroaralkyl; andeach R^(a), R^(b), R^(e), R^(g), R^(i), R^(j), R^(k), R^(m), R^(n),R^(o), R^(p), R^(q), R^(r), and R^(s) are independently hydrogen, alkyl,cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted heteroaryl, or optionally substitutedheteroaralkyl; or, independently of each other, each R^(i) and R^(j),R^(k) and R^(m), R^(n) and R^(o), and R^(p) and R^(q), together with thenitrogen atom to which they are attached form optionally substitutedheterocyclyl;

R¹, R², R³, and R⁴ are independently selected from hydrogen, alkyl,cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, cyano, hydroxy,hydroxylalkyl, amino, and aminoalkyl;

or one of R¹ and R² and R³ and R⁴, when attached to the same carbon,combine to form oxo, alkyldienyl, 3 to 6 membered cycloalkylene, or 4 to6 membered optionally substituted heterocyclylene;

R⁵ and R⁶ are independently selected from hydrogen, alkyl, cycloalkyl,halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, cyano, hydroxylalkyl,amino, and aminoalkyl, or wherein one of R⁵ and R⁶ is optionallysubstituted heterocyclyl and the other of R⁵ and R⁶ is selected fromhydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy,hydroxy, cyano, hydroxylalkyl, amino, and aminoalkyl;

L is bond, O, S, S(O), S(O)₂, or CR⁷R⁸ where R⁷ and R⁸ are independentlyhydrogen or alkyl;

Z¹ is a group of formula (a) or (b):

wherein:

R⁹ is hydrogen, alkyl, halo, hydroxy, amino, or haloalkyl;

R¹⁰ is hydrogen, alkyl, halo, hydroxy, hydroxyalkyl, —CD₂OH,alkylsulfoxide, alkylsulfonyl, amino, aminoalkyl, aminosulfonyl,aminocarbonyl, carboxy, cyano, or alkoxycarbonyl;

R¹³ is hydrogen, alkyl, halo, hydroxy, amino, or haloalkyl;

R¹⁴ is hydrogen, alkyl, or haloalkyl;

R¹¹ and R¹⁵ are selected from amino and aminoalkyl;

R¹² and R¹⁶ are selected from hydrogen, cyano, halo, alkyl, haloalkyl,alkoxy, haloalkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl,where alkyl, cycloalkyl, aryl, heterocyclyl and heteroaryl areoptionally substituted with one to three substituents independentlyselected from alkyl, halo, haloalkyl, haloalkoxy, alkoxy, and cyano;

or R¹¹ and R¹², and R¹⁵ and R¹⁶ together with the carbon atom to whichthey are attached form a ring of formula (c):

wherein:

e is 0, 1, or 2;

k is 0, 1, or 2 provided e+k is 1, 2, or 3;

q is 0, 1, or 2, or 3;

R¹⁷ and R¹⁸ are independently selected from hydrogen, alkyl, cycloalkyland haloalkyl,

each R¹⁹ is independently selected from hydrogen, alkyl, halo,haloalkyl, haloalkoxy, alkoxy, hydroxy, cyano, alkylsulfoxide,alkylsulfonyl, oxo, cycloalkyl, optionally substituted heterocyclyl, andoptionally substituted heteroaryl; or

when two R¹⁹ groups are attached to the same carbon atom, the two R¹⁹groups together with the carbon atom to which they are attached formcycloalkylene or heterocyclylene.

ring D is absent or present; wherein:

-   -   (i) when ring D is absent, then one of Q and W is CH₂, O, S,        S(O), S(O)₂, or NH; and the other of Q and W is CH₂; and    -   (ii) when ring D is present, then Q and W are independently N or        C provided only one of Q and W is N; and ring D is phenyl or a 5        or 6 membered heteroaryl ring which, including Q and W, contains        one to three heteroatoms independently selected from N, O, and S        and ring D is optionally be substituted with one or two        substituents independently selected from alkyl, cycloalkyl,        halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl,        cyano, amino, aminoalkyl, carboxy, and optionally substituted        heterocyclyl;    -   or a pharmaceutically acceptable salt thereof; provided that        when the compound of Formula (I), or a pharmaceutically        acceptable salt thereof, is a compound of formula

or a pharmaceutically acceptable salt thereof, where R⁹ is hydrogen, R¹⁰is other than hydrogen, amino, and aminoalkyl, and L, R¹¹ and R¹² are asdefined in Formula (IB); then

(i) when four of R¹, R², R³, R⁴, R⁵, and R⁶ are hydrogen and remainingtwo of R¹, R², R³, R⁴, R⁵, and R⁶ are independently selected fromhydrogen, alkyl, cycloalkyl, halo, haloalkyl, alkoxy, haloalkoxy,hydroxy, hydroxyalkyl, cyano, amino, and aminoalkyl; then Z is otherthan hydrogen, halo, alkyl, haloalkyl, cyano, cycloalkyl, heterocyclyl,heteroaryl(wherein cycloalkyl, heterocyclyl, and heteroaryl areoptionally substituted with one to three halo), —OR^(a), —S(O)R^(c),—S(O)₂R^(d), —NR^(e)C(O)R^(f), —NR^(g)SO₂R^(h), —OC(O)NR^(i)R^(j),—C(O)NR^(k)R^(m), —S(O)₂NR^(n)R^(o), —NR^(p)R^(q), —NR^(r)C(O)C(O)R^(s)(wherein R^(c), R^(d), R^(f), R^(h), and R^(s) are independently alkyl,cycloalkyl, cycloalkylalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substituted heteroaryl, oroptionally substituted heteroaralkyl; and R^(a), R^(e), R^(g), R^(i),Rj, R^(k), R^(m), R^(n), R^(o), R^(p), R^(q), and R^(r) areindependently hydrogen, alkyl, cycloalkylalkyl, hydroxyalkyl,alkoxyalkyl, aminoalkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted aryl, optionallysubstituted aralkyl, optionally substituted heteroaryl, or optionallysubstituted heteroaralkyl; or, independently of each other, each R^(i)and Rj, R^(k) and R^(m), R^(m) and R^(o), and R^(p) and R^(q), togetherwith the nitrogen atom to which they are attached form optionallysubstituted heterocyclyl) and Y-M (wherein (a) Y is bond or O and M isalkyl substituted with —OR^(a) or —NR^(p)R^(q) wherein R^(a) is hydrogenor alkyl and R^(p) and R^(q) are independently hydrogen, alkyl,hydroxyalkyl or alkoxyalkyl or R^(p) and R^(q) together with thenitrogen atom to which they are attached form optionally substitutedheterocyclyl and (b) Y is SO₂ and M is cycloalkyl (substituted with—OR), heteroaryl or heterocyclyl wherein heteroaryl or heterocyclyl areindependently substituted with —OR^(a), —S(O)₂R^(d), or —NR^(p)R^(q);where R^(a) is hydrogen or alkyl, R^(d) is alkyl, and R^(p) and R^(q)are independently hydrogen or alkyl and cycloalkyl is optionally furthersubstituted with one halo and heterocyclyl, and heteroaryl areoptionally further substituted with 1 or 2 halo);

(ii) when R⁵ and R⁶ are each hydrogen and two of R¹, R², R³, and R⁴ areeach hydrogen, and one of a) R¹ and R², and b) R³ and R⁴ are hydrogenand the other of a) R¹ and R², and b) R³ and R⁴ are attached to the samecarbon and are combined together to form alkylidene, 3 to 6 memberedcycloalkylene or 4 to 6 membered heterocyclylene, then Z is other thanhydrogen, alkyl, halo, haloalkyl, cyano, cycloalkyl, —OR^(a) (whereinR^(a) is hydrogen or alkyl), —NH₂, and -Y-M (wherein Y is bond and M isalkyl substituted with —OR, or

—NR^(p)R^(q) wherein each R^(a) is hydrogen or alkyl and R^(p) and R^(q)are independently hydrogen, alkyl, hydroxyalkyl or alkoxyalkyl or R^(p)and R^(q) together with the nitrogen atom to which they are attachedform optionally substituted heterocyclyl); and

(iii) when Z is hydrogen, one of a) R¹ and R², and b) R³ and R⁴ areattached to the same carbon and are combined together to form 3 to 6membered cycloalkylene or 4 to 6 membered heterocyclylene and three ofthe remaining R¹, R², R³, R⁴, R⁵, and R⁶ are hydrogen, then theremaining one of R¹, R², R³, R⁴, R⁵, and R⁶ is not hydrogen, alkyl,halo, haloalkyl, cyano, cycloalkyl, hydroxy, alkoxy, haloalkoxy,hydroxyalkyl, aminoalkyl, or amino.

In a fourth aspect, provided is a compound of Formula (IC):

wherein:

A and E are independently selected from a bond, CH₂, O, NH, S, andS(O)₂;

Z is hydrogen, alkyl, halo, haloalkyl, haloalkoxy, cyano, cycloalkyl,heterocyclyl, heteroaryl (wherein cycloalkyl, heterocyclyl, andheteroaryl are optionally substituted with one to three halo),—O(alk)_(y)R^(a), —O(alk)OR^(b), —S(O)R^(c), —S(O)₂R^(d),—NR^(e)C(O)R^(f), —NR^(g)SO₂R^(h), —OC(O)NR^(i)R^(j), —C(O)NR^(k)R^(m),—S(O)₂NR^(n)R^(o), —NR^(p)R^(q), —NR^(r)C(O)C(O)R^(s) or -Y-M (wherein Yis bond, O, or SO₂ and M is alkyl, haloalkyl, cycloalkyl, heterocyclyl,or heteroaryl wherein alkyl, haloalkyl, cycloalkyl, heterocyclyl andheteroaryl are substituted with —O(alk)_(y)R^(a), —O(alk)OR^(b),—S(O)R^(c), —S(O)₂R^(d), —NR^(e)C(O)R^(f), —NR^(g)SO₂R^(h),—OC(O)NR^(i)R^(j), —C(O)NR^(k)R^(m), —S(O)₂NR^(n)R^(o), —NRpR^(q), or—NR^(r)C(O)C(O)R^(s) and cycloalkyl, heterocyclyl, and heteroaryl areoptionally further substituted with 1 to 3 halo); wherein each y is 0 or1, each alk is alkylene, and each R^(e), R^(d), R^(f), R^(h), and R^(s)are independently alkyl, cycloalkyl, cycloalkylalkyl, optionallysubstituted heterocyclyl, optionally substituted heterocyclylalkyl,optionally substituted aryl, optionally substituted aralkyl, optionallysubstituted heteroaryl, or optionally substituted heteroaralkyl; andeach R^(a), R^(b), R^(e), R^(g), R^(i), R^(j), R^(k), R^(m), R^(n),R^(o), R^(p), R^(q), R^(r), and R^(s) are independently hydrogen, alkyl,cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted heteroaryl, or optionally substitutedheteroaralkyl; or, independently of each other, each R^(i) and R^(j),R^(k) and R^(m), R^(n) and R^(o), and R^(p) and R^(q), together with thenitrogen atom to which they are attached form optionally substitutedheterocyclyl;

R¹, R², R³, and R⁴ are independently selected from hydrogen, alkyl,cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, cyano, hydroxy,hydroxylalkyl, amino, and aminoalkyl;

or one of R¹ and R², and R³ and R⁴, when attached to the same carbon,combine to form oxo, alkyldienyl, 3 to 6 membered cycloalkylene, or 4 to6 membered optionally substituted heterocyclylene;

R⁵ and R⁶ are independently selected from hydrogen, alkyl, cycloalkyl,halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, cyano, hydroxylalkyl,amino, and aminoalkyl, or wherein one of R⁵ and R⁶ is optionallysubstituted heterocyclyl and the other is selected from hydrogen, alkyl,cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, cyano,hydroxylalkyl, amino, and aminoalkyl;

L is bond, O, S, S(O), S(O)₂, or CR⁷R⁸ where R⁷ and R⁸ are independentlyhydrogen or alkyl;

Z¹ is a group of formula (a) or (b):

wherein:

R⁹ is hydrogen, alkyl, halo, hydroxy, amino, or haloalkyl;

R¹⁰ is hydrogen, alkyl, halo, hydroxy, hydroxyalkyl, —CD₂OH,alkylsulfoxide, alkylsulfonyl, amino, aminoalkyl, aminosulfonyl,aminocarbonyl, carboxy, cyano, or alkoxycarbonyl;

R¹³ is hydrogen, alkyl, halo, hydroxy, amino, or haloalkyl;

R¹⁴ is hydrogen, alkyl, or haloalkyl;

R¹¹ and R¹⁵ are selected from amino and aminoalkyl;

R¹² and R¹⁶ are selected from hydrogen, cyano, halo, alkyl, haloalkyl,alkoxy, haloalkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl,where alkyl, cycloalkyl, aryl, heterocyclyl and heteroaryl areoptionally substituted with one to three substituents independentlyselected from alkyl, halo, haloalkyl, haloalkoxy, alkoxy, and cyano;

or R¹¹ and R¹², and R¹⁵ and R¹⁶ together with the carbon atom to whichthey are attached form a ring of formula (c):

wherein:

e is 0, 1, or 2;

k is 0, 1, or 2 provided e+k is 1, 2, or 3;

q is 0, 1, or 2, or 3;

R¹⁷ and R¹⁸ are independently selected from hydrogen, alkyl, cycloalkyl,and haloalkyl;

each R¹⁹ is independently selected from hydrogen, alkyl, halo,haloalkyl, haloalkoxy, alkoxy, hydroxy, cyano, alkylsulfoxide,alkylsulfonyl, oxo, cycloalkyl, optionally substituted heterocyclyl, andoptionally substituted heteroaryl; or

when two R¹⁹ groups are attached to the same carbon atom, the two R¹⁹groups together with the carbon atom to which they are attached formcycloalkylene or heterocyclylene.

ring D is absent or present; wherein:

-   -   (i) when ring D is absent, then one of Q and W is CH₂, O, S,        S(O), S(O)₂, or NH; and the other of Q and W is CH₂; and    -   (ii) when ring D is present, then Q and W are independently N or        C provided only one of Q and W is N; and ring D is phenyl or a 5        or 6 membered heteroaryl ring which, including Q and W, contains        one to three heteroatoms independently selected from N, O, and S        and ring D is optionally substituted with one or two        substituents independently selected from alkyl, cycloalkyl,        halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl,        cyano, amino, aminoalkyl, carboxy, and optionally substituted        heterocyclyl;        or a pharmaceutically acceptable salt thereof; provided that the        compound of Formula (IC) is not a compound of any one of        embodiments 37 to 42 and 45 to 63 disclosed herein below and        embodiments contained therein, or a pharmaceutically acceptable        salt thereof.

In a fifth aspect, provided a pharmaceutical composition comprising acompound of Formula (I), (IA), (IB), or (IC) (or any of the embodimentsthereof described herein), or a pharmaceutically acceptable saltthereof; and a pharmaceutically acceptable excipient.

In a sixth aspect, provided is a method of treating a disease treatableby inhibition of SHP2 in a patient which method comprises administeringto the patient, preferably a patient in need of such treatment, atherapeutically effective amount thereof a compound of Formula (I),(IA), (IB), or (IC) (or any of the embodiments thereof describedherein), or comprises administering to the patient, preferably a patientin of such treatment, a pharmaceutical composition comprising a compoundof Formula (I), (IA), (IB), or (IC) (or any of the embodiments thereofdescribed herein) and a pharmaceutically acceptable excipient. In oneembodiment, the disease is cancer. In another embodiment, the disease iscancer selected from lung, stomach, liver, colon, kidney, breast,pancreatitis, juvenile myelomonocytic leukemias, neurolastoma, melanoma,and acute myeloid leukemia. In one embodiment, the disease is selectedfrom Noonan syndrome and Leopard syndrome.

In a seventh aspect, provided is a compound of Formula (I), (IA), (IB),or (IC) (or any embodiments thereof described herein) or apharmaceutically acceptable salt thereof for use as a medicament.

In a eighth aspect provided is the use of a compound of Formula (I),(IA), (IB), or (IC) or a pharmaceutically acceptable salt thereof (andany embodiments thereof disclosed herein) in the manufacture of amedicament for treating a disease in a patient in need of such treatmentin which the activity of SHP2 contributes to the pathology and/orsymptoms of the disease.

In a ninth aspect provided is a method of inhibiting SHP2 which methodcomprises contacting SHP2 with a compound of Formula (I), (IA), (IB), or(IC) (or any of the embodiments thereof described herein) or apharmaceutically acceptable salt thereof; or contacting SHP2 with apharmaceutical composition comprising a compound of the presentdisclosure (or any of the embodiments thereof described herein) or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient.

In a tenth aspect, provided is an intermediate of Formula (V):

wherein:

Q is halo or SH;

A and E are independently selected from a bond, CH₂, O, NH, S, andS(O)₂;

Z is hydrogen, alkyl, halo, haloalkyl, haloalkoxy, cyano, cycloalkyl,heterocyclyl, heteroaryl (wherein cycloalkyl, heterocyclyl, andheteroaryl are optionally substituted with one to three halo),—O(alk)_(y)R^(a), —O(alk)OR^(b), —S(O)R^(c), —S(O)₂R^(d),—NR^(e)C(O)R^(f), —NR^(g)SO₂R^(b), —OC(O)NR^(i)R^(j), —C(O)NR^(k)R^(m),—S(O)₂NR^(n)R^(o), —NR^(p)R^(q), —NR^(r)C(O)C(O)R^(s) or -Y-M (wherein Yis bond, O, or SO₂ and M is alkyl, haloalkyl, cycloalkyl, heterocyclyl,or heteroaryl wherein alkyl, haloalkyl, cycloalkyl, heterocyclyl andheteroaryl are substituted with —O(alk)_(y)R^(a),

—O(alk)_(y)OR^(b), —S(O)R^(c), —S(O)₂R^(d), —NR^(e)C(O)R^(f),—NR^(g)SO₂R^(h), —OC(O)NR^(i)R^(j), —C(O)NR^(k)R^(m), —S(O)₂NR^(n)R^(o),—NR^(p)R^(q), or —NR^(r)C(O)C(O)R^(s) and cycloalkyl, heterocyclyl, andheteroaryl are optionally further substituted with 1 to 3 halo); whereineach y is 0 or 1, each alk is alkylene, and each R^(c), R^(d), R^(f),R^(h), and R^(s) are independently alkyl, cycloalkyl, cycloalkylalkyl,optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted heteroaryl, or optionally substitutedheteroaralkyl; and each R^(a), R^(b), R^(e), R^(g), R^(i), Rj, R^(k),R^(m), R^(n), R^(o), R^(p), R^(q), R^(r), and R^(s) are independentlyhydrogen, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl,aminoalkyl, optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted heteroaryl, or optionally substitutedheteroaralkyl; or, independently of each other, each R^(i) and Rj, R^(k)and R^(m), R^(n) and R^(o), and R^(p) and R^(q), together with thenitrogen atom to which they are attached form optionally substitutedheterocyclyl;

R¹, R², R³, and R⁴ are independently selected from hydrogen, alkyl,cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, cyano, hydroxy,hydroxylalkyl, amino, and aminoalkyl;

or one of R¹ and R², and R³ and R⁴, when attached to the same carbon,combine to form oxo, alkyldienyl, 3 to 6 membered cycloalkylene, or 4 to6 membered optionally substituted heterocyclylene;

R⁵ and R⁶ are independently selected from hydrogen, alkyl, cycloalkyl,halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, cyano, hydroxylalkyl,amino, and aminoalkyl, or wherein one of R⁵ and R⁶ is optionallysubstituted heterocyclyl and the other of R⁵ and R⁶ is selected fromhydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy,hydroxy, cyano, hydroxylalkyl, amino, and aminoalkyl;

or an acceptable salt thereof.

In a first embodiment of the tenth aspect, Q is halo. In a subembodimentof the first embodiment, Q is chloro, bromo, or iodo.

In a second embodiment of the tenth aspect, Q is -S⁻M⁺ where M⁺ metalion. In a subembodiment of the second embodiment, M⁺ is sodium orpotassium.

In a third embodiment of any one of tenth aspect, first and secondembodiments and subembodiments contained therein,

In a fourth embodiment of any one of tenth aspect, first, second, andthird embodiments and subembodiments contained therein, A, E, Z, R¹, R²,R³, R⁴ R⁵, and R⁶ are as defined in the embodiment section herein below.

DETAILED DESCRIPTION

Certain structures provided herein are drawn with one or more floatingsubstituents. Unless provided otherwise or otherwise clear from thecontext, the substituent(s) may be present on any atom of the ring towhich it is attached, where chemically feasible and valency rulespermitting. For example, in the structure:

the R³, R⁴, and Z substituents can replace any hydrogen on the6-membered ring which comprises group A, including one or both of thehydrogens of the CH₂ group when A is CH₂, and including the hydrogen ofNH when A is NH. In another example, in the ring of formula (c):

when ring D is absent and Q and/or W is CH₂, one or both of thehydrogens are optionally replaced by one or two R¹⁹ groups.

Definitions

Unless otherwise stated, the following terms used in the specificationand claims are defined for the purposes of this Application and have thefollowing meaning:

“Alkyl” means a linear saturated monovalent hydrocarbon radical of oneto six carbon atoms or a branched saturated monovalent hydrocarbonradical of three to six carbon atoms, e.g., methyl, ethyl, propyl,2-propyl, butyl, pentyl, and the like. It will be recognized by a personskilled in the art that the term “alkyl” may include “alkylene” groups.

“Alkylene” means a linear saturated divalent hydrocarbon radical of oneto six carbon atoms or a branched saturated divalent hydrocarbon radicalof three to six carbon atoms unless otherwise stated e.g., methylene,ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene,pentylene, and the like.

“Alkenyl” means a linear monovalent hydrocarbon radical of two to sixcarbon atoms or a branched monovalent hydrocarbon radical of three tosix carbon atoms containing a double bond, e.g., propenyl, butenyl, andthe like.

“Alkyldienyl” is alkenyl as defined above that is attached via theterminal divalent carbon. For example, in the compound below:

the alkyldienyl group is enclosed by the box which is indicated by thearrow.

“Alkylthio” means a —SR radical where R is alkyl as defined above, e.g.,methylthio, ethylthio, and the like.

“Alkylsulfonyl” means a —SO₂R radical where R is alkyl as defined above,e.g., methylsulfonyl, ethylsulfonyl, and the like.

“Alkylsulfoxide” means a —SOR radical where R is alkyl as defined above,e.g., methylsulfoxide, ethylsulfoxide, and the like.

“Amino” means a —NH₂.

“Alkylamino” means a —NHR radical where R is alkyl as defined above,e.g., methylamino, ethylamino, propylamino, or 2-propylamino, and thelike.

“Acylamino” means a —NHC(O)R radical where R is alkyl as defined above,e.g., acetylamino, propionoylamino, and the like.

“Aminoalkyl” means a linear monovalent hydrocarbon radical of one to sixcarbon atoms or a branched monovalent hydrocarbon radical of three tosix carbons substituted with —NR′R″ where R′ and R″ are independentlyhydrogen, alkyl, haloalkyl, hydroxyalkyl, or alkoxyalkyl, or R′ and R″together with the nitrogen atom to which they are attached formoptionally substituted heterocyclyl, each as defined herein, e.g.,aminomethyl, aminoethyl, methylaminomethyl, morpholinylethyl,piperazin-1-ylethyl, and the like.

“Alkoxy” means a —OR radical where R is alkyl as defined above, e.g.,methoxy, ethoxy, propoxy, or 2-propoxy, n-, iso-, or tert-butoxy, andthe like.

“Alkoxyalkyl” means a linear monovalent hydrocarbon radical of one tosix carbon atoms or a branched monovalent hydrocarbon radical of threeto six carbons substituted with at least one alkoxy group, such as oneor two alkoxy groups, as defined above, e.g., 2-methoxyethyl, 1-, 2-, or3-methoxypropyl, 2-ethoxyethyl, and the like.

“Alkoxycarbonyl” means a —C(O)OR radical where R is alkyl as definedabove, e.g., methoxycarbonyl, ethoxycarbonyl, and the like.

“Aryl” means a monovalent monocyclic or bicyclic aromatic hydrocarbonradical of 6 to 10 ring atoms e.g., phenyl or naphthyl.

“Aralkyl” means -(alkylene)-R where R is aryl as defined above e.g.,benzyl or phenethyl.

“Cycloalkyl” means a monocyclic saturated monovalent hydrocarbon radicalof three to ten carbon atoms optionally substituted with one or twosubstituents independently selected from alkyl, halo, alkoxy, hydroxy,and cyano, unless stated otherwise. Examples include, but are notlimited to, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and thelike.

“Cycloalkylalkyl” means a -(alkylene)-R radical where R is cycloalkyl asdefined above, e.g., cyclopropylmethyl, cyclohexylmethyl, and the like.

“Cycloalkylene” means, unless stated otherwise, a monocyclic saturateddivalent hydrocarbon radical of three to six carbon atoms optionallysubstituted with one or two substituents independently selected fromalkyl, halo, alkoxy, hydroxy, and cyano, each as defined herein.Examples include, but are not limited to, cyclopropylene, cyclobutylene,cyclopentylene, or cyclohexylene, and the like.

“Carboxy” means —C(O)OH.

“Dialkylamino” means a —NRR′ radical where R and R′ are alkyl as definedabove, e.g., dimethylamino, methylethylamino, and the like.

“Aminosulfonyl” means a —SO₂NRR′ radical where R and R′ areindependently hydrogen, alkyl, haloalkyl, hydroxyalkyl, or alkoxyalkyl,each as defined herein, e.g., aminosulfonyl, methylaminosulfonyl,dimethylaminosulfonyl, and the like.

“Aminocarbonyl” means a —CONRR′ radical where R and R′ are independentlyhydrogen, alkyl, haloalkyl, hydroxyalkyl, or alkoxyalkyl, each asdefined herein, e.g., aminocarbonyl, methylaminocarbonyl,dimethylaminocarbonyl, ethylmethylaminocarbonyl, and the like.

“Aminocarboxy” means a —C(O)ONRR′ radical where R and R′ areindependently hydrogen, alkyl, haloalkyl, hydroxyalkyl, or alkoxyalkyl,each as defined herein, e.g., aminocarbonyloxy, methylaminocarbonyloxy,dimethylaminocarbonyloxy, and the like.

“Halo” means fluoro, chloro, bromo, or iodo, preferably fluoro orchloro.

“Haloalkyl” means alkyl radical as defined above, which is substitutedwith one or more halogen atoms, e.g., one to five halogen atoms, such asfluorine or chlorine, including those substituted with differenthalogens, e.g., —CH₂Cl, —CF₃, —CHF₂, —CH₂CF₃, —CF₂CF₃, —CF(CH₃)₂, andthe like. When the alkyl is substituted with only fluoro, it can bereferred to in this Application as fluoroalkyl.

“Haloalkoxy” means a —OR radical where R is haloalkyl as defined abovee.g., —OCF₃, —OCHF₂, and the like. When R is haloalkyl where the alkylis substituted with only fluoro, it is referred to in this Applicationas fluoroalkoxy.

“Hydroxyalkyl” means a linear monovalent hydrocarbon radical of one tosix carbon atoms or a branched monovalent hydrocarbon radical of threeto six carbons substituted with one or two hydroxy groups, provided thatif two hydroxy groups are present they are not both on the same carbonatom. Representative examples include, but are not limited to,hydroxymethyl, 2-hydroxy-ethyl, 2-hydroxypropyl, 3-hydroxypropyl,1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl,4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl,2,3-dihydroxybutyl, 3,4-dihydroxybutyl and2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl,2,3-dihydroxypropyl, and 1-(hydroxymethyl)-2-hydroxyethyl.

“Heterocyclyl” means a saturated or unsaturated monovalent monocyclic orbicyclic ring of 4 to 10 ring atoms in which one, two, or three ringatoms are heteroatom selected from N, O, and S(O)_(n), where n is aninteger from 0 to 2, the remaining ring atoms being C. Additionally, oneor two ring carbon atoms in the heterocyclyl ring can optionally bereplaced by a —CO— group. More specifically the term heterocyclylincludes, but is not limited to, pyrrolidino, piperidino,homopiperidino, 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholino,piperazino, tetrahydro-pyranyl, thiomorpholino,6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one,6,7-dihydropyrimido[2,1-c][1,4]oxazin-4(9H)-one, and the like. When theheterocyclyl ring is unsaturated it can contain one or two ring doublebonds provided that the ring is not aromatic. When the heterocyclylgroup contains at least one nitrogen atom, it is also referred to hereinas heterocycloamino and is a subset of the heterocyclyl group.

“Heterocyclylene” means, unless stated otherwise, a saturated orunsaturated divalent monocyclic or bicyclic ring of 4 to 6 ring atoms inwhich one, two, or three ring atoms are heteroatom selected from N, O,and S(O)_(n), where n is an integer from 0 to 2, the remaining ringatoms being C. Heterocyclylene can be optionally substituted with one ortwo substituents independently selected from alkyl, halo, haloalkyl,haloalkoxy, cyano, or hydroxy, each as defined herein.

“Heteroaryl” means a monovalent monocyclic or bicyclic aromatic radicalof 5 to 10 ring atoms, unless otherwise stated, where one or more, (inone embodiment, one, two, or three), ring atoms are heteroatom selectedfrom N, O, or S, the remaining ring atoms being carbon. Representativeexamples include, but are not limited to, pyrrolyl, thienyl, thiazolyl,imidazolyl, furanyl, indolyl, isoindolyl, oxazolyl, isoxazolyl,benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, pyridinyl,pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, and thelike. As defined herein, the terms “heteroaryl” and “aryl” are mutuallyexclusive. When the heteroaryl ring contains 5- or 6 ring atoms it isalso referred to herein as 5- or 6-membered heteroaryl.

“Heteroaralkyl” means -(alkylene)-R where R is heteroaryl as definedabove e.g., benzyl or phenethyl.

The term “oxo,” as used herein, alone or in combination, refers to ═(O).

When needed, any definition herein may be used in combination with anyother definition to describe a composite structural group. Byconvention, the trailing element of any such definition is that whichattaches to the parent moiety. For example, the composite groupalkoxyalkyl means that an alkoxy group attached to the parent moleculethrough an alkyl group.

The present disclosure also includes protected derivatives of compoundsof Formula (I), (IA), (IB), or (IC) or embodiments thereof. For example,when compounds of Formula (I), (IA), (IB), or (IC) contain groups suchas hydroxy, carboxy, thiol or any group containing a nitrogen atom(s),these groups can be protected with a suitable protecting groups. Acomprehensive list of suitable protective groups can be found in T. W.Greene, Protective Groups in Organic Synthesis, 5^(th) Ed., John Wiley &Sons, Inc. (2014), the disclosure of which is incorporated herein byreference in its entirety. The protected derivatives of compounds ofFormula (I), (IA), (IB), or (IC) can be prepared by methods well knownin the art.

The present disclosure also includes polymorphic forms and deuteratedforms of the compounds of Formula (I), (IA), (IB), or (IC). The term“prodrug” refers to a compound that is made more active in vivo. Certaincompounds disclosed herein may also exist as prodrugs, as described inHydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, andEnzymology (Testa, Bernard and Mayer, Joachim M. Wiley-VHCA, Zurich,Switzerland 2003). Prodrugs of the compounds described herein arestructurally modified forms of the compound that readily undergochemical changes under physiological conditions to provide the activecompound. Prodrugs are often useful because, in some situations, theymay be easier to administer than the compound, or parent drug. They may,for instance, be bioavailable by oral administration whereas the parentdrug is not. A wide variety of prodrug derivatives are known in the art,such as those that rely on hydrolytic cleavage or oxidative activationof the prodrug. An example, without limitation, of a prodrug would be acompound which is administered as an ester (the “prodrug”), but then ismetabolically hydrolyzed to the carboxylic acid, the active entity.Additional examples include peptidyl derivatives of a compound.

A “pharmaceutically acceptable salt” of a compound of Formula (I), (IA),(IB), or (IC) means a salt that is pharmaceutically acceptable and thatpossesses the desired pharmacological activity of the parent compound.Such salts include:

acid addition salts, formed with inorganic acids such as hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, andthe like; or formed with organic acids such as formic acid, acetic acid,propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolicacid, pyruvic acid, lactic acid, malonic acid, succinic acid, malicacid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoicacid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid,4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, muconic acid, and the like; or salts formed when anacidic proton present in the parent compound either is replaced by ametal ion, e.g., an alkali metal ion, an alkaline earth ion, or analuminum ion; or coordinates with an organic base such as ethanolamine,diethanolamine, triethanolamine, tromethamine, N-methylglucamine, andthe like. It is understood that the pharmaceutically acceptable saltsare non-toxic. Additional information on suitable pharmaceuticallyacceptable salts can be found in Remington's Pharmaceutical Sciences,17th ed., Mack Publishing Company, Easton, Pa., 1985, which isincorporated herein by reference in its entirety.

The compounds of Formula (I), (IA), (IB), or (IC) may have asymmetriccenters. Compounds of Formula (I), (IA), (IB), or (IC) containing anasymmetrically substituted atom may be isolated in optically active orracemic forms. Individual stereoisomers of compounds can be preparedsynthetically from commercially available starting materials whichcontain chiral centers or by preparation of mixtures of enantiomericproducts followed by separation such as conversion to a mixture ofdiastereomers followed by separation or recrystallization,chromatographic techniques, direct separation of enantiomers on chiralchromatographic columns, or any other appropriate method known in theart. All chiral, diastereomeric, all mixtures of chiral or diasteromericforms, and racemic forms are within the scope of this disclosure, unlessthe specific stereochemistry or isomeric form is specifically indicated.It will also be understood by a person of ordinary skill in the art thatwhen a compound is denoted as (R) stereoisomer, it may contain thecorresponding (S) stereoisomer as an impurity and vice versa.

Certain compounds of Formula (I), (IA), (IB), or (IC) can exist astautomers and/or geometric isomers. All possible tautomers and cis andtrans isomers, as individual forms and mixtures thereof are within thescope of this disclosure. Additionally, as used herein the term alkylincludes all the possible isomeric forms of said alkyl group albeit onlya few examples are set forth. Furthermore, when the cyclic groups suchas aryl, heteroaryl, heterocyclyl are substituted, they include all thepositional isomers albeit only a few examples are set forth.Furthermore, all hydrates of a compound of Formula (I), (IA), (IB), or(IC) are within the scope of this disclosure.

The compounds of Formula (I), (IA), (IB), or (IC) may also containunnatural amounts of isotopes at one or more of the atoms thatconstitute such compounds. Unnatural amounts of an isotope may bedefined as ranging from the amount found in nature to an amount 100% ofthe atom in question. that differ only in the presence of one or moreisotopically enriched atoms. Exemplary isotopes that can be incorporatedinto compounds of the present invention, such as a compound of Formula(I), (IA), (IB), or (IC) (and any embodiment thereof disclosed hereinincluding specific compounds) include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine,such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹³O, ¹⁷O, ¹⁸O, ³²P, ³³P, ³⁵S,¹⁸F, ³⁶Cl, ¹²³I, and ¹²⁵I, respectively. Isotopically labeled compounds(e.g., those labeled with ³H and ¹⁴C) can be useful in compound orsubstrate tissue distribution assays. Tritiated (i.e., 3H) and carbon-14(i.e., ¹⁴C) isotopes can be useful for their ease of preparation anddetectability. Further, substitution with heavier isotopes such asdeuterium (i.e., ²H) may afford certain therapeutic advantages resultingfrom greater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements). In some embodiments, in compoundsdisclosed herein, including in Table 1 below one or more hydrogen atomsare replaced by ²H or ³H, or one or more carbon atoms are replaced by¹³C- or ¹⁴C-enriched carbon. Positron emitting isotopes such as ¹⁵O,¹³N, ¹¹C, and ¹⁵F are useful for positron emission tomography (PET)studies to examine substrate receptor occupancy. Isotopically labeledcompounds can generally be prepared by following procedures analogous tothose disclosed in the Schemes or in the Examples herein, bysubstituting an isotopically labeled reagent for a non-isotopicallylabeled reagent.

“Optionally substituted aryl” means aryl that is optionally substitutedwith one, two, or three substituents independently selected from alkyl,hydroxyl, cycloalkyl, carboxy, alkoxycarbonyl, hydroxy, alkoxy,alkylthio, alkylsulfonyl, amino, alkylamino, dialkylamino, halo,haloalkyl, haloalkoxy, and cyano.

“Optionally substituted aralkyl” means -(alkylene)-R where R isoptionally substituted aryl as defined above.

“Optionally substituted heteroaryl” means heteroaryl as defined abovethat is optionally substituted with one, two, or three substituentsindependently selected from alkyl, alkylthio, alkylsulfonyl, hydroxyl,cycloalkyl, carboxy, alkoxycarbonyl, hydroxy, alkoxy, halo, haloalkyl,haloalkoxy, amino, alkylamino, dialkylamino, and cyano.

“Optionally substituted heteroaralkyl” means -(alkylene)-R where R isoptionally substituted heteroaryl as defined above.

“Optionally substituted heterocyclyl” means heterocyclyl as definedabove that is optionally substituted with one, two, or threesubstituents independently selected from alkyl, alkylthio,alkylsulfonyl, hydroxyl, cycloalkyl, carboxy, alkoxycarbonyl, hydroxy,hydroxyalkyl, alkoxy, alkoxyalkyl, aminoalkyl, halo, haloalkyl,haloalkoxy, and cyano.

“Optionally substituted heterocyclylalkyl” means -(alkylene)-R where Ris optionally substituted heterocyclyl as defined above.

A “pharmaceutically acceptable carrier or excipient” means a carrier oran excipient that is useful in preparing a pharmaceutical compositionthat is generally safe, non-toxic and neither biologically nor otherwiseundesirable, and includes a carrier or an excipient that is acceptablefor veterinary use as well as human pharmaceutical use. “Apharmaceutically acceptable carrier/excipient” as used in thespecification and claims includes both one and more than one suchexcipient.

The term “about,” as used herein, is intended to qualify the numericalvalues which it modifies, denoting such a value as variable within amargin of error. When no particular margin of error, such as a standarddeviation to a mean value given in a chart or table of data, is recited,the term “about” should be understood to mean that range which wouldencompass ±10%, preferably ±5%, the recited value and the range isincluded.

The term “disease” as used herein is intended to be generallysynonymous, and is used interchangeably with, the terms “disorder,”“syndrome,” and “condition” (as in medical condition), in that allreflect an abnormal condition of the human or animal body or of one ofits parts that impairs normal functioning, is typically manifested bydistinguishing signs and symptoms, and causes the human or animal tohave a reduced duration or quality of life.

The term “combination therapy” means the administration of two or moretherapeutic agents to treat a disease or disorder described in thepresent disclosure. Such administration encompasses co-administration ofthese therapeutic agents in a substantially simultaneous manner, such asin a single capsule having a fixed ratio of active ingredients or inmultiple, separate capsules for each active ingredient. In addition,such administration also encompasses use of each type of therapeuticagent in a sequential manner. In either case, the treatment regimen willprovide beneficial effects of the drug combination in treating theconditions or disorders described herein.

The term “patient” is generally synonymous with the term “subject” andincludes all mammals including humans. Examples of patients includehumans, livestock such as cows, goats, sheep, pigs, and rabbits, andcompanion animals such as dogs, cats, rabbits, and horses. Preferably,the patient is a human.

“Treating” or “treatment” of a disease includes:

(1) preventing the disease, i.e. causing the clinical symptoms of thedisease not to develop in a mammal that may be exposed to or predisposedto the disease but does not yet experience or display symptoms of thedisease;

(2) inhibiting the disease, i.e., arresting or reducing the developmentof the disease or its clinical symptoms; or

(3) relieving the disease, i.e., causing regression of the disease orits clinical symptoms. In one embodiment, treating or treatment means(2) or (3) above.

A “therapeutically effective amount” means the amount of a compound ofFormula (I), (IA), (IB), or (IC) or a pharmaceutically acceptable saltthereof that, when administered to a patient for treating a disease, issufficient to affect such treatment for the disease. The“therapeutically effective amount” will vary depending on the compound,the disease and its severity and the age, weight, etc., of the mammal tobe treated.

The terms “inhibiting” and “reducing,” or any variation of these termsin relation of SHP2, includes any measurable decrease or completeinhibition to achieve a desired result. For example, there may be adecrease of about, at most about, or at least about 5%, 10%, 15%, 20%,25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%,95%, 99%, or more, or any range derivable therein, reduction of SHP2activity compared to normal.

Representative compounds of Formula (I) are disclosed in Table (1) below

TABLE 1 Com- pound # Structure Name 1

(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((S)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2- yl)methanol 2

(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((R)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2- yl)methanol 3

(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((6aS,8S)-8-fluoro-6a,7,8,9-tetrahydro-6H-pyrido[3,2- b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)methanol 4

(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((6aS,8R)-8-fluoro-6a,7,8,9-tetrahydro-6H-pyrido[3,2- b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)methanol 5

(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((6aS,8S)-8- methoxy-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4- yl)thio)pyrazin-2-yl)methanol6

(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((6aS,8R)-8- methoxy-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin- 4-yl)thio)pyrazin-2-yl)methanol7

(6aS,8S)-4-((5-((3S,4S)-4-amino-3- methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)- 6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin- 8-ol 8

(6aS,8R)-4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)- 6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin- 8-ol 9

(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((6aR,8R)-8- methoxy-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin- 4-yl)thio)pyrazin-2-yl)methanol10

(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((6aR,8S)-8- methoxy-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin- 4-yl)thio)pyrazin-2-yl)methanol11

(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((6aS,8S)-8-(((S)-tetrahydrofuran-3-yl)oxy)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2- yl)methanol 12

(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((6aS,8S)-8-(((R)-tetrahydrofuran-3-yl)oxy)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2- yl)methanol 13

(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((6aS,8S)-8-(oxetan-3-yloxy)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin- 4-yl)thio)pyrazin-2-yl)methanol14

(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((6aS,8S)-8-(methoxymethoxy)-6a,7,8,9-tetrahydro- 6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2- yl)methanol 15

(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((6aS,8S)-8-(2-methoxyethoxy)-6a,7,8,9-tetrahydro- 6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2- yl)methanol 16

(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((6aS,8S)-8- (cyclopropylmethoxy)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2- yl)methanol 17

(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((S)-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin]-4′-yl)thio)pyrazin-2-yl)methanol 18

(6aS,8S)-4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-8- methyl-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin- 8-ol 19

(6aS,8R)-4-((5-((3S,4S)-4-amino-3- methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-8-methyl-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin- 8-ol 20

(6aS,8S)-4-((5-((3S,4S)-4-amino-3- methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(hydroxymethyl)pyrazin-2- yl)thio)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine- 8-carbonitrile 21

(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((6aS,8S)-8-(methylsulfonyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin- 4-yl)thio)pyrazin-2-yl)methanol22

(6aS,8S)-4-((5-((3S,4S)-4-amino-3- methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)- 6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin- 8-yl carbamate 23

(6aS,8R)-4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)- 6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-8- yl carbamate 24

(6-(((6aS,8S)-8-(1H-pyrazol-1-yl)- 6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)-3-((3S,4S)-4-amino-3-methyl- 2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)methanol 25

(6-(((6aS,8R)-8-(1H-pyrazol-1-yl)- 6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)-3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin- 2-yl)methanol 26

(3-((3S,4S)-4-amino-3-methyl-2-oxa-8- azaspiro[4.5]decan-8-yl)-6-(((R)-6a,7,9,10-tetrahydro-6H- [1,4]oxazino[4,3-d]pyrido[3,2-b][1,4]oxazin-4-yl)thio)pyrazin-2- yl)methanol 27

(3-((3S,4S)-4-amino-3-methyl-2-oxa-8- azaspiro[4.5]decan-8-yl)-6-(((S)-6a,7,9,10-tetrahydro-6H- [1,4]oxazino[4,3-d]pyrido[3,2-b][1,4]oxazin-4-yl)thio)pyrazin-2- yl)methanol 28

4-((5-((3S,4S)-4-amino-3-methyl-2- oxa-8-azaspiro[4.5]decan-8-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)- 6a,7,9,10-tetrahydro-6H-pyrido[3,2-b][1,4]thiazino[4,3- d][1,4]oxazine 8,8-dioxide 29

(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((6aS,8S)-8-(methoxymethyl)-6a,7,8,9-tetrahydro- 6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2- yl)methanol 30

(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((6aS,8R)-8-(methoxymethyl)-6a,7,8,9-tetrahydro- 6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2- yl)methanol 31

(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((6aS,8S)-8-((methoxymethoxy)methyl)-6a,7,8,9- tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin- 4-yl)thio)pyrazin-2-yl)methanol32

(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((6aS,8S)-8-((2-methoxyethoxy)methyl)-6a,7,8,9- tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin- 4-yl)thio)pyrazin-2-yl)methanol33

(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((6aS,8S)-8-((cyclopropylmethoxy)methyl)-6a,7,8,9- tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin- 4-yl)thio)pyrazin-2-yl)methanol34

(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((6aS,8S)-8-((oxetan-3-ylmethoxy)methyl)-6a,7,8,9- tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin- 4-yl)thio)pyrazin-2-yl)methanol35

(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((S)-2- amino-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin- 4-yl)thio)pyrazin-2-yl)methanolformate 36

(3-((S)-5-amino-5,7- dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)-6-(((6aS,8S)-8-(methoxymethyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4- yl)thio)pyrazin-2-yl)methanol37

(3-((S)-5-amino-5,7- dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)-6-(((6aS,8R)-8-(methoxymethyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin- 4-yl)thio)pyrazin-2-yl)methanol38

(3-((S)-5-amino-13-oxa-9- azadispiro[3.1.56.24]tridecan-9-yl)-6-(((6aS,8S)-8-(methoxymethyl)-6a,7,8,9- tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin- 4-yl)thio)pyrazin-2-yl)methanol39

(3-((S)-5-amino-13-oxa-9- azadispiro[3.1.56.24]tridecan-9-yl)-6-(((6aS,8S)-8-((methoxymethoxy)methyl)- 6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4- yl)thio)pyrazin-2-yl)methanol40

(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((6aS,8S)-8-(((methoxymethoxy)methoxy)methyl)- 6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin- 4-yl)thio)pyrazin-2-yl)methanol41

(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((6aS,8S)-8-(hydroxymethyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin- 4-yl)thio)pyrazin-2-yl)methanol42

(3S,4S)-8-(5-(((6aS,8S)-8- ((methoxymethoxy)methyl)-6a,7,8,9-tetrahydro-6H- pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa- 8-azaspiro[4.5]decan-4-amine 43

(3S,4S)-8-(5-(((6aS,8S)-8- (methoxymethyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa- 8-azaspiro[4.5]decan-4-amine 44

(3S,4S)-8-(6-amino-5-(((6aS,8S)-8- ((methoxymethoxy)methyl)-6a,7,8,9-tetrahydro-6H- pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa- 8-azaspiro[4.5]decan-4-amine 45

(3S,4S)-8-(6-amino-5-(((6aS,8S)-8-(methoxymethyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa- 8-azaspiro[4.5]decan-4-amine 46

(S)-1′-(5-(((6aS,8S)-8- ((methoxymethoxy)methyl)-6a,7,8,9-tetrahydro-6H- pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine 47

(S)-1′-(6-amino-5-(((6aS,8S)-8- ((methoxymethoxy)methyl)-6a,7,8,9-tetrahydro-6H- pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine 48

(3-((S)-5-amino-5,7- dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)-6-(((6aS,8S)-8-((methoxymethoxy)methyl)-6a,7,8,9- tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin- 4-yl)thio)pyrazin-2-yl)methanol49

(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((6aS,8S)-8-((methoxymethoxy)methyl)-6a,7,8,9- tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin- 4-yl)thio)-5-methylpyrazin-2-yl)methanol 50

(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((6aS,8R)-8-((methoxymethoxy)methyl)-6a,7,8,9- tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin- 4-yl)thio)pyrazin-2-yl)methanol51

(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((6aR,8S)-8-((methoxymethoxy)methyl)-6a,7,8,9- tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin- 4-yl)thio)pyrazin-2-yl)methanol52

(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((6aR,8R)-8-((methoxymethoxy)methyl)-6a,7,8,9- tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin- 4-yl)thio)pyrazin-2-yl)methanol53

(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-((6aS,8S)-8-(methoxymethyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin- 4-yl)pyrazin-2-yl)methanol 54

(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-((6aS,8S)-8-((methoxymethoxy)methyl)-6a,7,8,9- tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin- 4-yl)pyrazin-2-yl)methanolContemplated compounds of Formula (I) are disclosed in Table 2 below

II-1

6-amino-2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-5-(((6aS,8S)-8-((methoxymethoxy)methyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)-3-methylpyrimidin-4(3H)-one II-2

2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-5-(((6aS,8S)-8-((methoxymethoxy)methyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)-3-methyl-pyrimidin-4(3H)-one II-3

6-amino-2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-5-(((6aS,8S)-8-(methoxymethyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)-3-methylpyrimidin-4(3H)-one II-4

2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-5-(((6aS,8S)-8-(methoxymethyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)-3-methylpyrimidin- 4(3H)-oneII-5

(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((6aS,8S)-8-(methoxymethyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)-5-methyl-pyrazin-2-yl)methanol II-6

(S)-1′-(5-(((6aS,8S)-8-(methoxymethyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidin]-5-amine II-7

(S)-1′-(6-amino-5-(((6aS,8S)-8-(methoxymethyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine II-8

(3S,4S)-8-(5-(((6aS,8S)-8-((cyclopropylmethoxy)methyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine II-9

(3S,4S)-8-(6-amino-5-(((6aS,8S)-8-((cyclopropylmethoxy)methyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine II-10

6-amino-2-((3S,45)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-5-(((6aS,8S)-8-((cyclopropylmethoxy)methyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)-3-methylpyrimidin-4(3H)-one II-11

2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-5-(((6aS,8S)-8-((cyclopropylmethoxy)methyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)-3-methylpyrimidin-4(3H)-one II-12

(3-((S)-5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)-6-(((6aS,8R)-8-((methoxymethoxy)methyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)methanol II-13

(3-((S)-5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)-6-(((6aR,8R)-8-((methoxymethoxy)methyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)methanol II-14

(3-((S)-5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)-6-(((6aR,8S)-8-((methoxymethoxy)methyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)methanol II-15

(S)-1′-(5-(((6aS,8R)-8-((methoxymethoxy)methyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine II-16

(S)-1′-(5-(((6aR,8R)-8-((methoxymethoxy)methyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine II-17

(S)-1′-(5-(((6aR,8S)-8-((methoxymethoxy)methyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine II-18

(S)-1′-(6-amino-5-(((6aS,8R)-8-((methoxymethoxy)methyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine II-19

(S)-1′-(6-amino-5-(((6aR,8R)-8-((methoxymethoxy)methyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine II-20

(S)-1′-(6-amino-5-(((6aR,8S)-8-((methoxymethoxy)methyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine

EMBODIMENTS

In further embodiments 1-36 below, the present disclosure includes:

1. In embodiment 1, provided is a compound of Formula (I), (IA), (IB),or (IC) as described in the Summary above, or a pharmaceuticallyacceptable salt thereof.

In a first subembodiment of embodiment 1, the compound is a compound ofFormula (I), or a pharmaceutically acceptable salt thereof. In a secondsubembodiment of embodiment 1, the compound is a compound of Formula(IA), or a pharmaceutically acceptable salt thereof. In a thirdsubembodiment of embodiment 1, the compound is a compound of Formula(IB), or a pharmaceutically acceptable salt thereof. In a fourthsubembodiment of embodiment 1, the compound is a compound of Formula(IC), or a pharmaceutically acceptable salt thereof.

2. In embodiment 2, the compound of any one of embodiment 1 andsubembodiments contained within embodiment 1, or a pharmaceuticallyacceptable salt thereof is wherein the has a structure of formula (II):(i.e., Z¹ is a group of formula (a))

3. In embodiment 3, the compound of any one of embodiments 1 and 2 andsubembodiment contained therein, and or a pharmaceutically acceptablesalt thereof is wherein the compound has a structure of Formula (HA):

4. In embodiment 5, the compound of any one of embodiment 1 andsubembodiment contained within embodiment 1, or a pharmaceuticallyacceptable salt thereof is wherein the compound has a structure offormula (III) (i.e., Z¹ is a group of formula (b))

5. In embodiment 5, the compound of any one of embodiment 1 and 4 andsubembodiments contained therein, or a pharmaceutically acceptable saltthereof is wherein the compound has a structure of Formula (TIA):

6. In embodiment 6, the compound of any one of embodiments 1 to 5 andsubembodiment contained therein, or a pharmaceutically acceptable saltthereof is wherein E is O and A is CH₂ or bond.

7. In embodiment 7, the compound of any one of embodiments 1 to 5 andsubembodiment contained therein, or a pharmaceutically acceptable saltthereof is wherein E is O and A is bond.

8. In embodiment 8, the compound of embodiment 3 and subembodimentcontained therein, or a pharmaceutically acceptable salt thereof has astructure of formula (IIB):

9. In embodiment 9, the compound of embodiment 5 and subembodimentcontained therein, or a pharmaceutically acceptable salt thereof has thestructure of formula (IIIB):

10. In embodiment 10, the compound of any one of embodiments 1 to 9 andsubembodiment contained therein, or a pharmaceutically acceptable saltthereof is wherein Z is hydrogen, alkyl, halo, haloalkyl, haloalkoxy,cyano, cycloalkyl, heterocyclyl, heteroaryl (wherein cycloalkyl,heterocyclyl, and heteroaryl are optionally substituted with one tothree halo), —O(alk)_(y)R^(a), —O(alk)OR^(b), —S(O)₂R^(d),—OC(O)NR^(i)R^(j), —S(O)₂NRnR^(o), —NR^(p)R^(q), or -Y-M (wherein Y isbond, O, or SO₂ and M is alkyl, haloalkyl, cycloalkyl, heterocyclyl, orheteroaryl wherein alkyl, haloalkyl, cycloalkyl, heterocyclyl andheteroaryl are substituted with —O(alk)_(y)R^(a), —O(alk)OR^(b),—S(O)R^(d), or —NR^(p)R^(q) and cycloalkyl, heterocyclyl, and heteroarylare optionally further substituted with 1 to 3 halo).

11. In embodiment 11, the compound of any one of embodiments 1 to 9 andsubembodiment contained therein, or a pharmaceutically acceptable saltthereof is wherein Z is -Y-M (wherein Y is bond or O and M is alkyl,haloalkyl, cycloalkyl, heterocyclyl, or heteroaryl wherein alkyl,haloalkyl, cycloalkyl, heterocyclyl and heteroaryl are substituted with—O(alk)OR^(b), —S(O)R^(d), —NR^(e)C(O)R^(f), —NR^(g)SO₂R^(h),—OC(O)NR^(i)R^(j), —C(O)NR^(k)R^(m), or —S(O)₂NR^(n)R^(o).

12. In embodiment 12, the compound of any one of embodiments 1 to 9 andsubembodiment contained therein, or a pharmaceutically acceptable saltthereof is wherein Z is -Y-M (wherein Y is bond and M is alkyl,haloalkyl, cycloalkyl, heterocyclyl, or heteroaryl wherein alkyl,haloalkyl, cycloalkyl, heterocyclyl and heteroaryl are substituted with—O—R^(a) where R^(a) is alkyl, cycloalkyl, cycloalkylalkyl, aminoalkyl,optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted aryl, or optionallysubstituted heteroaryl.

13. In embodiment 13, the compound of any one of embodiments 1 to 9 andsubembodiment contained therein, or a pharmaceutically acceptable saltthereof is wherein Z is -Y-M (wherein Y is bond and M is alkyl,haloalkyl, cycloalkyl, heterocyclyl, or heteroaryl wherein alkyl,haloalkyl, cycloalkyl, heterocyclyl and heteroaryl are substituted with—O(alk)OR^(a) where R^(a) is alkyl, cycloalkyl, cycloalkylalkyl,aminoalkyl, optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted aryl, or optionallysubstituted heteroaryl.

14. In embodiment 14, the compound of any one of embodiments 1 to 9 andsubembodiment contained therein, or a pharmaceutically acceptable saltthereof is wherein Z is —OR^(a) where R^(a) is alkyl, cycloalkyl,cycloalkylalkyl, aminoalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substituted aryl,or optionally substituted heteroaryl.

15. In embodiment 15, the compound of any one of embodiments 1 to 9 andsubembodiment contained therein, or a pharmaceutically acceptable saltthereof is wherein Z is —O(alk)OR^(b) where R^(b) is alkyl, cycloalkyl,cycloalkylalkyl, aminoalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substituted aryl,or optionally substituted heteroaryl.

16. In embodiment 16, the compound of any one of embodiments 1 to 9 andsubembodiment contained therein, or a pharmaceutically acceptable saltthereof is wherein Z is hydrogen, fluoro, cyano, methoxy, hydroxy,cyclopentyloxy, tetrahydrofuran-3-yloxy, oxetan-3-yloxy,methoxymethyloxy, methoxyethyloxy, methylsulfonyl, aminocarbonyloxy,pyrazol-1-yl, hydroxymethyl, methoxymethyl, ethoxymethyl,methoxymethyloxymethyl, ethoxymethyloxymethyl, methoxyethyloxymethyl,cyclopropylmethyloxy, or oxetan-3-ylmethyloxymethyl.

17. In embodiment 17, the compound of any one of embodiments 1 to 9 andsubembodiment contained therein, or a pharmaceutically acceptable saltthereof is wherein Z is methoxymethyloxy, methoxyethyloxy,methoxymethyl, methxoymethyloxymethyl, ethoxymethyloxymethyl,methoxyethyloxymethyl, cyclopropylmethyloxy, oroxetan-3-ylmethyloxymethyl.

18. In embodiment 18, the compound of any one of embodiments 1 to 9 andsubembodiment contained therein, or a pharmaceutically acceptable saltthereof is wherein Z is methoxymethyl, methoxymethyloxymethyl,ethoxymethyloxymethyl, methoxyethyloxymethyl,cyclopropylmethyloxymethyl, or oxetan-3-ylmethyloxymethyl.

19. In embodiment 18, the compound of any one of embodiments 1 to 9 andsubembodiment contained therein, or a pharmaceutically acceptable saltthereof is wherein Z is fluoro.

20. In embodiment 20, the compound of any one of embodiments 1 to 19 andsub-embodiments contained therein, or a pharmaceutically acceptable saltthereof is wherein R⁹ and R¹³ are hydrogen.

21. In embodiment 21, the compound of any one of embodiments 1 to 19 andsub-embodiment contained therein, or a pharmaceutically acceptable saltthereof is wherein R⁹ and R¹³ are amino.

21A. In embodiment 21A, the compound of any one of embodiments 1 to 19and sub-embodiment contained therein, or a pharmaceutically acceptablesalt thereof is wherein R⁹ and R¹³ are methyl.

21B. In embodiment 21B, the compound of any one of embodiments 1 to 19and sub-embodiment contained therein, or a pharmaceutically acceptablesalt thereof is wherein R⁹ and R¹³ are independently hydrogen, alkyl, oramino.

22. In embodiment 22, the compound of any one of embodiments 1 to 21Band sub-embodiments contained therein, or a pharmaceutically acceptablesalt thereof is wherein L is S.

23. In embodiment 23, the compound of any one of embodiments 1 to 21Band sub-embodiments contained therein, or a pharmaceutically acceptablesalt thereof is wherein L is S(O) or S(O)₂.

24. In embodiment 24, the compound of any one of embodiments 1 to 21Band sub-embodiments contained therein, or a pharmaceutically acceptablesalt thereof is wherein L is bond.

25. In embodiment 25, the compound of any one of embodiments 1 to 24 andsub-embodiments contained therein, or a pharmaceutically acceptable saltthereof is wherein L is CR⁷R⁸ where R⁵ and R⁶ are independently hydrogenor alkyl. In one sub-embodiment, of embodiment 10, L is CH₂. In anothersub-embodiment of embodiment 10, L is C(CH₃)₂.

26. In embodiment 26, the compound of any one of embodiments 1 to 3,6-8, and 10 to 25 and sub-embodiments contained therein, or apharmaceutically acceptable salt thereof is wherein R¹⁰ is hydroxyalkyl.In a first sub-embodiment of embodiment 11, R¹⁰ is hydroxymethyl.

27. In embodiment 27, the compound of any one of embodiments 1 to 3,6-8, and 10 to 25 and sub-embodiments contained therein, or apharmaceutically acceptable salt thereof is wherein R¹⁰ isalkylsulfonyl. In a first sub-embodiment of embodiment 27, R² ismethylsulfonyl or ethylsulfonyl.

27A. In embodiment 27A, the compound of any one of embodiments 1 to 3,6-8, and 10 to 25 and sub-embodiments contained therein, or apharmaceutically acceptable salt thereof is wherein R¹⁰ is hydrogen.

28. In embodiment 28, the compound of any one of embodiments 11 to 25and sub-embodiments contained therein, or a pharmaceutically acceptablesalt thereof is wherein R¹⁴ is hydrogen.

29. In embodiment 29, the compound of any one of embodiments 11 to 25and sub-embodiments contained therein, or a pharmaceutically acceptablesalt thereof is wherein R¹⁴ is -alkyl. In a first subembodiment, R¹⁴ ismethyl.

30. In embodiment 30, the compound of any one of embodiments 1 to 29 andsub-embodiments contained therein, or a pharmaceutically acceptable saltthereof is wherein:

R¹¹ and R¹⁵ are selected from amino and aminoalkyl; and R¹² and R¹⁶ areselected from hydrogen, cyano, halo, alkyl, haloalkyl, alkoxy,haloalkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl, where alkyl,cycloalkyl, aryl, heterocyclyl and heteroaryl are optionally substitutedwith one to three substituents independently selected from alkyl, halo,haloalkyl, haloalkoxy, alkoxy, and cyano. In a sub-embodiment ofembodiment 30, R¹¹ and R¹³ are aminomethyl, and R¹² and R¹⁶ are methyl.

31. In embodiment 31, the compound of any one of embodiments 1 to 29 andsub-embodiments contained therein, or a pharmaceutically acceptable saltthereof is wherein: R¹ and R¹², and R¹⁵ and R¹⁶ together with the carbonatom to which they are attached form a ring of formula (c):

In a first subembodiment of embodiment 31, ring of formula (c) is:

In a second subembodiment of embodiment 31, ring of formula (c) is

32. In embodiment 32, the compound of any one of 1 to 29 andsub-embodiments contained therein, or a pharmaceutically acceptable saltthereof is wherein R¹¹ and R¹², and R¹⁵ and R¹⁶ together with the carbonatom to which they are attached form a ring of formula (c):

In a first embodiment of embodiment 32, ring of formula c is:

33. In embodiment 33, the compound of any one of embodiments 1 to 32 andsub-embodiments contained therein, or a pharmaceutically acceptable saltthereof is wherein R¹, R², R³, and R⁴ are independently selected fromhydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, cyan, or hydroxy,amino. In a first subembodiment 33, one of R¹, R², R³, and R⁴ ishydrogen and the remaining three of R¹, R², R³, and R⁴ are independentlyselected from hydrogen, methyl, fluoro, methoxy, hydroxy, or amino. In asecond subembodiment 33, two or three of R¹, R², R³, and R⁴ are hydrogenand the remaining one or two of R¹, R², R³, and R⁴ are independentlyselected from hydrogen, methyl, fluoro, methoxy, hydroxy, or amino. In athird subembodiment 33, R¹, R², R³, and R⁴ are hydrogen.

34. In embodiment 34, the compound of any one of embodiments 1 to 32 andsub-embodiments contained therein, or a pharmaceutically acceptable saltthereof is wherein R⁵ is hydrogen, alkyl, halo, or amino and R⁶ ishydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, or cyano.

35. In embodiment 35, the compound of any one of embodiments 1 to 32 andsub-embodiments contained therein, or a pharmaceutically acceptable saltthereof is wherein R⁵ is hydrogen, chloro, methyl, or amino and R⁶ ishydrogen, methyl, chloro, trifluoromethyl, trifluoromethoxy, or methoxy.

36. In embodiment 34, the compound of any one of embodiments 1 to 32 andsub-embodiments contained therein, or a pharmaceutically acceptable saltthereof is R⁵ and R⁶ are hydrogen.

It is understood that the embodiments set forth above include allcombination of embodiments and subembodiments listed therein. Forexample, the ring of formula (c) listed in embodiment 31 and first andsecond sub-embodiments of embodiment 31, can independently be combinedwith one or more of the embodiments 1-30 and 32-36 and/or subembodimentscontained therein.

Additional embodiments include Embodiments 37-63 below:

37. A compound of Formula (I′):

wherein:

A is

substituted with R^(a), R^(b), and/or R^(c) wherein R^(a) and R^(b) areindependently selected from hydrogen, alkyl, amino, cycloalkyl,alkyldienyl, alkenyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy,hydroxyalkyl, alkoxyalkyl, cyano, aminoalkyl, carboxy, andalkoxycarbonyl and R^(c) is hydrogen, alkyl, halo, hydroxy, alkoxy,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, —S(O)R, S(O)₂R, —C(O)R, —OR′,—NR′C(O)R, —NR′SO₂R, —OC(O)NR′R″, —C(O)NR′R″, —S(O)₂NR′R″, —NR′R″, or—NR′C(O)C(O)R where R is alkyl, cycloalkyl, cycloalkylalkyl, optionallysubstituted heterocyclyl, optionally substituted heterocyclylalkyl,optionally substituted aryl, optionally substituted aralkyl, optionallysubstituted heteroaryl, or optionally substituted heteroaralkyl, and R′and R″ are independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl,aminoalkyl, cycloalkylalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substituted heteroaryl, oroptionally substituted heteroaralkyl or R′ and R″ together with thenitrogen atom to which they are attached form optionally substitutedheterocyclyl; or when R^(c) and R^(a) are attached to the same carbon ofcycloalkyl or fused heteroaryl ring, then R^(c) and R^(a) together withthe carbon atom to which they are attached form cycloalkylene orheterocyclylene;

or A is has the structure (d):

where:

t is 0, 1 or 2;

ring E is 4 to 7 membered heterocycle containing 1 or 2 heteroatomsindependently selected from O, N, S, and SO₂ where the remaining atomsare carbon; and W is O, CH₂, or N; substituted with R^(a), R^(b), and/orR^(c) wherein R^(a) and R^(b) are independently selected from hydrogen,amino, alkyl, alkyldienyl, alkenyl, halo, haloalkyl, alkoxy, haloalkoxy,hydroxy, hydroxyalkyl, cyano, aminoalkyl, carboxy, and alkoxycarbonyland R^(e) is hydrogen, alkyl, halo, hydroxy, or alkoxy; or when R^(a)and R^(c) are attached to the same carbon atom, R^(a) and R^(c) togethertogether with the carbon atom to which they are attached formcycloalkylene or heterocyclylene

Q¹ is N or CR¹ wherein R¹ is hydrogen or deuterium;

Q² is N or CH, or CD;

R² is alkyl, halo, hydroxy, hydroxyalkyl, —CD₂OH, alkylsulfoxide,alkylsulfonyl, aminosulfonyl, aminocarbonyl, carboxy, cyano, oralkoxycarbonyl;

L is bond, O, S, S(O), S(O)₂, or CR⁵R⁶ where R⁵ and R⁶ are independentlyhydrogen or alkyl; and

is a ring of formula (a) or (b):

wherein:

m is 0, 1; or 2;

n is 0, 1, or 2 wherein when n is 2 then one of the CH₂ can be replacedwith O, S, or SO₂;

provided m+n is 1, 2, or 3;

k is 0, 1 or 2;

z is 0, 1, or 2;

each R^(d) is independently hydrogen, alkyl, or halogen;

R^(e) and R^(e1) are independently hydrogen, alkyl, halogen, haloalkyl,alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, cyano or oxo; or

when R^(e) and R^(e1) are attached to the same carbon atom, then R^(e)and R^(e1) together with the carbon atom to which they are attached formcycloalkylene or heterocyclylene;

R^(f) and R^(g) are independently hydrogen, alkyl, or haloalkyl;

each R^(h) is independently alkyl, halo, haloalkyl, alkoxy,hydroxyalkyl, alkoxyalkyl, hydroxy, cyano, or oxo; or

when one R^(h) is connected to carbon 2 or 3 of the piperidine (b) ringand the second R^(h) is attached to carbon 5 or 6 of the piperidine (b)ring, the nitrogen atom being position 1, then the first and secondR^(h) combine to form alkylene chain;

ring D is phenyl or a 5 or 6 membered heteroaryl ring which, including Xand X′, contains one to three heteroatoms independently selected from N,O, and S and ring D can optionally be substituted with one or two groupsindependently selected from alkyl, halo, haloalkyl, alkoxy, haloalkoxy,hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, carboxy, cycloalkyl,heterocyclyl, heteroaryl, and acylamino;

X and X¹ are independently N or C provided only one of X and X¹ can beN;

R³ is amino or aminoalkyl;

R⁴ is alkyl, cycloalkylalkyl, halo, hydroxy, amino, alkoxycarbonyl,hydroxyalkyl, alkoxyalkyl, arylalkyl, heterocyclalkyl, cycloalkylalkyl,heterocyclalkyl, 5 or 6 membered heteroaryl, or 4 to 6 memberedheterocyclyl wherein heteroaryl or heterocyclyl by itself or as part ofaralkyl or heteroaralkyl is substituted with R^(i) and/or R^(j)independently selected from hydrogen, alkyl, halo, haloalkyl,haloalkoxy, alkoxy, hydroxy, cyano, amino, aminoalkyl, alkylsulfoxide,or alkylsulfonyl; or

R³ and R⁴ together with the carbon atom to which they are attached forma ring of formula (c):

wherein:

m1 is 0, 1; or 2;

n1 is 0, 1, or 2; provided m1+n1 is 1, 2, or 3;

R^(k) and R^(m) are independently hydrogen, alkyl, or haloalkyl;

one of Y and Z is CH₂, O, S, S(O), S(O)₂, or NH; and the other of X andY is CH₂; and wherein ring of formula (c) is substituted with R^(n)and/or R^(o) independently selected from hydrogen, alkyl, alkyldienyl,alkenyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, cyano,alkylsulfoxide, alkylsulfonyl, oxo, cycloalkyl, heterocyclyl, andheteroaryl; or

when R^(n) and R^(o) are attached to the same carbon atom, then R^(n)and R^(o) together with the carbon atom to which they are attached formcycloalkylene or heterocyclylene; or

a pharmaceutically acceptable salt thereof.

38. The compound of embodiment 37 having a structure of Formula (I′A):

wherein:

A is

substituted with R^(a), R^(b), and/or R^(c) wherein R^(a) and R^(b) areindependently selected from hydrogen, alkyl, amino, cycloalkyl,alkyldienyl, alkenyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy,hydroxyalkyl, cyano, aminoalkyl, carboxy, and alkoxycarbonyl and R^(e)is hydrogen, alkyl, halo, hydroxy, alkoxy, optionally substitutedheterocyclyl, optionally substituted aryl, optionally substitutedheteroaryl, —S(O)R, S(O)₂R,—C(O)R, —NR′C(O)R, —NR′SO₂R, —C(O)NR′R″, —S(O)₂NR′R″, —NR′R″, or—NR′C(O)C(O)R where R is alkyl, cycloalkyl, cycloalkylalkyl, optionallysubstituted heterocyclyl, optionally substituted heterocyclylalkyl,optionally substituted aryl, optionally substituted aralkyl, optionallysubstituted heteroaryl, or optionally substituted heteroaralkyl, and R′and R″ are independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl,aminoalkyl, cycloalkylalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substituted heteroaryl, oroptionally substituted heteroaralkyl or R′ and R″ together with thenitrogen atom to which they are attached form optionally substitutedheterocyclyl; or when R^(c) and R^(a) are attached to the same carbon ofcycloalkyl or fused heteroaryl ring, then R^(c) and R^(a) together withthe carbon atom to which they are attached form cycloalkylene orheterocyclylene;

A has the structure (d):

where:

t is 0, 1 or 2;

ring E is 4 to 7 membered heterocycle containing 1 or 2 heteroatomsindependently selected from O, N, S, and SO₂ where the remaining atomsare carbon; and W is O, CH₂, or N; optionally substituted with R^(a),R^(b), and/or R^(c) wherein R^(a) and R^(b) are independently selectedfrom hydrogen, amino, alkyl, alkyldienyl, alkenyl, halo, haloalkyl,alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, cyano, aminoalkyl, carboxy,and alkoxycarbonyl and R^(e) is hydrogen, alkyl, halo, hydroxy, oralkoxy; or when R^(a) and R^(c) are attached to the same carbon atom,R^(a) and R^(c) together together with the carbon atom to which they areattached form cycloalkylene or heterocyclylene;

Q¹ is N or CR¹ wherein R¹ is hydrogen or deuterium;

Q² is N or CH, or CD;

R² is alkyl, halo, hydroxy, hydroxyalkyl, —CD₂OH, alkylsulfoxide,alkylsulfonyl, aminosulfonyl, aminocarbonyl, carboxy, cyano, oralkoxycarbonyl;

L is bond, O, S, S(O), S(O)₂, or CR⁵R⁶ where R⁵ and R⁶ are independentlyhydrogen or alkyl; and

is a ring of formula (a) or (b):

wherein:

m is 0, 1; or 2;

n is 0, 1, or 2; provided m+n is 1, 2, or 3;

k is 0, 1 or 2

z is 0, 1, or 2

each R^(d) is independently hydrogen, alkyl, or halogen;

R^(e) is hydrogen, alkyl, halogen, haloalkyl, alkoxy, haloalkoxy,hydroxy, hydroxyalkyl, cyano or oxo;

R^(f) and R^(g) are independently hydrogen, alkyl, or haloalkyl;

each R^(h) is independently alkyl, halo, haloalkyl, alkoxy,hydroxyalkyl, alkoxyalkyl, hydroxy, cyano, or oxo; or

when one R^(h) is connected to carbon 2 or 3 of the piperidine (b) ringand the second R^(h) is attached to carbon 5 or 6 of the piperidine (b)ring, the nitrogen atom being position 1, then the first and secondR^(h) combine to form alkylene chain;

ring D is phenyl or a 5 or 6 membered heteroaryl ring which, including Xand X¹, contains one to three heteroatoms independently selected from N,O, and S and ring D can optionally be substituted with one or two groupsindependently selected from alkyl, halo, haloalkyl, alkoxy, haloalkoxy,hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, carboxy, cycloalkyl,heterocyclyl, heteroaryl, and acylamino;

X and X¹ are independently N or C provided only one of X and X¹ can beN;

R³ is amino or aminoalkyl;

R⁴ is alkyl, cycloalkylalkyl, halo, hydroxy, amino, alkoxycarbonyl,hydroxyalkyl, alkoxyalkyl, arylalkyl, heterocyclalkyl, cycloalkylalkyl,heterocyclalkyl, 5 or 6 membered heteroaryl, or 4 to 6 memberedheterocyclyl wherein heteroaryl or heterocyclyl by itself or as part ofaralkyl or heteroaralkyl is substituted with R^(i) and/or R^(j)independently selected from hydrogen, alkyl, halo, haloalkyl,haloalkoxy, alkoxy, hydroxy, cyano, amino, aminoalkyl, alkylsulfoxide,or alkylsulfonyl; or

R³ and R⁴ together with the carbon atom to which they are attached forma ring of formula (c):

wherein:

m1 is 0, 1; or 2;

n1 is 0, 1, or 2; provided m1+n1 is 1, 2, or 3;

R^(k) and R^(m) are independently hydrogen, alkyl, or haloalkyl;

one of Y and Z is CH₂, O, S, S(O), S(O)₂, or NH; and the other of X andY is CH₂; and wherein ring of formula (c) is substituted with R^(n)and/or R^(o) independently selected from hydrogen, alkyl, alkyldienyl,alkenyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, cyano,alkylsulfoxide, alkylsulfonyl, oxo, cycloalkyl, heterocyclyl, andheteroaryl; or

a pharmaceutically acceptable salt thereof.

39. A compound of Formula (I′B):

wherein:

A is

substituted with R^(a), R^(b), and/or R^(c) wherein R^(a) and R^(b) areindependently selected from hydrogen, alkyl, halo, haloalkyl, alkoxy,haloalkoxy, hydroxy, hydroxyalkyl, cyano, aminoalkyl, carboxy, andalkoxycarbonyl and R^(o) is hydrogen, alkyl, halo, hydroxy, alkoxy,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, —S(O)R, S(O)₂R, —C(O)R, —NR′C(O)R,—NR′SO₂R, —C(O)NR′R″, —S(O)₂NR′R″, —NR′R″, or —NR′C(O)C(O)R where R isalkyl, cycloalkyl, cycloalkylalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substituted heteroaryl, oroptionally substituted heteroaralkyl, and R′ and R″ are independentlyhydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cycloalkylalkyl,optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted heteroaryl, or optionally substitutedheteroaralkyl or R′ and R″ together with the nitrogen atom to which theyare attached form optionally substituted heterocyclyl;

Q¹ is N or CR¹ wherein R¹ is hydrogen or deuterium;

Q² is N or CH, or CD;

R² is alkyl, halo, hydroxy, hydroxyalkyl, —CD₂OH, alkylsulfoxide,alkylsulfonyl, aminosulfonyl, aminocarbonyl, carboxy, cyano, oralkoxycarbonyl;

L is bond, O, S, S(O), S(O)₂, or CR⁵R⁶ where R⁵ and R⁶ are independentlyhydrogen or alkyl; and

is a ring of formula (a) or (b):

wherein:

m is 0, 1; or 2;

n is 0, 1, or 2; provided m+n is 1, 2, or 3;

k is 0, 1 or 2

z is 0, 1, or 2

each R^(d) is independently hydrogen, alkyl, or halogen;

R^(e) is hydrogen, alkyl, halogen, haloalkyl, alkoxy, haloalkoxy,hydroxy, hydroxyalkyl, cyano or oxo;

R^(f) and R^(g) are independently hydrogen, alkyl, or haloalkyl;

each R^(h) is independently alkyl, halo, haloalkyl, alkoxy,hydroxyalkyl, alkoxyalkyl, hydroxy, cyano, or oxo; or

when one R^(h) is connected to carbon 2 or 3 of the piperidine (b) ringand the second R^(h) is attached to carbon 5 or 6 of the piperidine (b)ring, the nitrogen atom being position 1, then the first and secondR^(h) combine to form alkylene chain;

ring D is phenyl or a 5 or 6 membered heteroaryl ring which, including Xand X¹, contains one to three heteroatoms independently selected from N,O, and S and ring D can optionally be substituted with one or two groupsindependently selected from alkyl, halo, haloalkyl, alkoxy, haloalkoxy,hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, carboxy, cycloalkyl,heterocyclyl, heteroaryl, and acylamino;

X and X¹ are independently N or C provided only one of X and X¹ can beN;

R³ is amino or aminoalkyl;

R⁴ is alkyl, cycloalkylalkyl, halo, hydroxy, amino, alkoxycarbonyl,hydroxyalkyl, alkoxyalkyl, arylalkyl, heterocyclalkyl, cycloalkylalkyl,heterocyclalkyl, 5 or 6 membered heteroaryl, or 4 to 6 memberedheterocyclyl wherein heteroaryl or heterocyclyl by itself or as part ofaralkyl or heteroaralkyl is substituted with R^(i) and/or R^(j)independently selected from hydrogen, alkyl, halo, haloalkyl,haloalkoxy, alkoxy, hydroxy, cyano, amino, aminoalkyl, alkylsulfoxide,or alkylsulfonyl; or

R³ and R⁴ together with the carbon atom to which they are attached forma ring of formula (c):

wherein:

m1 is 0, 1; or 2;

n1 is 0, 1, or 2; provided m1+n1 is 1, 2, or 3;

R^(k) and R^(m) are independently hydrogen, alkyl, or haloalkyl; one ofY and Z is CH₂, O, S, S(O), S(O)₂, or NH; and the other of X and Y isCH₂; and wherein ring of formula (c) is substituted with R^(n) and/orR^(o) independently selected from hydrogen, alkyl, halo, haloalkyl,haloalkoxy, alkoxy, hydroxy, cyano, alkylsulfoxide, alkylsulfonyl, oxo,cycloalkyl, heterocyclyl, and heteroaryl; or

a pharmaceutically acceptable salt thereof.

40. A compound of Formula (I′C):

wherein:

A is

substituted with R^(a), R^(b), and/or R^(c) wherein R^(a) and R^(b) areindependently selected from hydrogen, alkyl, amino, cycloalkyl,alkyldienyl, alkenyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy,hydroxyalkyl, cyano, aminoalkyl, carboxy, and alkoxycarbonyl and R^(e)is hydrogen, alkyl, halo, hydroxy, alkoxy, optionally substitutedheterocyclyl, optionally substituted aryl, optionally substitutedheteroaryl, —NHCOR, or—NR′R″ where R is alkyl, cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl, optionally substitutedheteroaryl, or optionally substituted heteroaralkyl, and R′ and R″ areindependently hydrogen or alkyl or R′ and R″ together with the nitrogenatom to which they are attached form optionally substitutedheterocyclyl; or when R^(e) and R^(a) are attached to the same carbon ofcycloalkyl or fused heteroaryl ring, then R^(c) and R^(a) together withthe carbon atom to which they are attached form cycloalkylene orheterocyclylene;

A has the structure (d):

where:

t is 0, 1 or 2;

ring E is 4 to 7 membered heterocycle containing 1 or 2 heteroatomsindependently selected from O, N, S, and SO₂ where the remaining atomsare carbon; and W is O, CH₂, or N; optionally substituted with R^(a),R^(b), and/or R^(c) wherein R^(a) and R^(b) are independently selectedfrom hydrogen, amino, alkyl, alkyldienyl, alkenyl, halo, haloalkyl,alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, cyano, aminoalkyl, carboxy,and alkoxycarbonyl and R^(c) is hydrogen, alkyl, halo, hydroxy, oralkoxy; or when R^(a) and R^(c) are attached to the same carbon atom,R^(a) and R^(c) together together with the carbon atom to which they areattached form cycloalkylene or heterocyclylene.

Q¹ is N or CR¹ wherein R¹ is hydrogen or deuterium;

Q² is N, CH, or CD;

R² is alkyl, halo, hydroxy, hydroxyalkyl, —CD₂OH, alkylsulfoxide,alkylsulfonyl, aminosulfonyl, aminocarbonyl, carboxy, cyano, oralkoxycarbonyl;

L is bond, O, S, SO, SO₂, or CR⁵R⁶ where R⁵ and R⁶ are independentlyhydrogen or alkyl; and

is a ring of formula (a) or (b):

wherein:

m is 0, 1; or 2;

n is 0, 1, or 2; provided m+n is 1, 2, or 3;

R^(d) is hydrogen or alkyl;

R^(e) is hydrogen, alkyl, halogen, or oxo;

R^(h) is independently alkyl, halo, haloalkyl, alkoxy, hydroxyalkyl,alkoxyalkyl, hydroxy, cyano, or oxo;

ring D is phenyl or a 5 or 6 membered heteroaryl ring which, including Xand X¹, contains one to three heteroatoms independently selected from N,O, or S and ring D can optionally be substituted with alkyl;

X and X¹ are independently N or C provided only one of X and X¹ can beN;

R³ is amino or aminoalkyl;

R⁴ is alkyl, cycloalkylalkyl, halo, hydroxy, amino, alkoxycarbonyl,hydroxyalkyl, alkoxyalkyl, 5 or 6 membered heteroaryl, or 4 to 6membered heterocyclyl wherein heteroaryl or heterocyclyl is substitutedwith R^(i) and/or R^(j) independently selected from hydrogen, alkyl,halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, cyano, alkylsulfoxide, oralkylsulfonyl; or

R³ and R⁴ together with the carbon atom to which they are attached forma ring of formula (c):

wherein:

m1 is 0, 1; or 2;

n1 is 0, 1, or 2; provided m1+n1 is 1, 2, or 3;

one of Y and Z is CH₂, O, S, SO, SO₂, or NH; and the other of X and Y isCH₂; and wherein ring of formula (c) is substituted with R^(o) and/or Rindependently selected from hydrogen, alkyl, alkyldienyl, alkenyl, halo,haloalkyl, haloalkoxy, alkoxy, hydroxy, cyano, alkylsulfoxide,alkylsulfonyl, or oxo; or

a pharmaceutically acceptable salt thereof.

41. A compound of Formula (I′D):

wherein:

A is

substituted with R^(a), R^(b), and/or R^(c) wherein R^(a) and R^(b) areindependently selected from hydrogen, alkyl, halo, haloalkyl, alkoxy,haloalkoxy, hydroxy, hydroxyalkyl, cyano, aminoalkyl, carboxy, andalkoxycarbonyl and R^(c) is hydrogen, alkyl, halo, hydroxy, alkoxy,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, —NHCOR, or —NR′R″ where R is alkyl,cycloalkyl, optionally substituted heterocyclyl, optionally substitutedaryl, optionally substituted heteroaryl, or optionally substitutedheteroaralkyl, and R′ and R″ are independently hydrogen or alkyl or R′and R″ together with the nitrogen atom to which they are attached formoptionally substituted heterocyclyl;

Q¹ is N or CR¹ wherein R¹ is hydrogen or deuterium;

Q² is N, CH, or CD;

R² is alkyl, halo, hydroxy, hydroxyalkyl, —CD₂OH, alkylsulfoxide,alkylsulfonyl, aminosulfonyl, aminocarbonyl, carboxy, cyano, oralkoxycarbonyl;

L is bond, O, S, SO, SO₂, or CR⁵R⁶ where R⁵ and R⁶ are independentlyhydrogen or alkyl; and

is a ring of formula (a) or (b):

wherein:

m is 0, 1; or 2;

n is 0, 1, or 2; provided m+n is 1, 2, or 3;

R^(d) is hydrogen or alkyl;

R^(e) is hydrogen, alkyl, halogen, or oxo;

R^(h) is independently alkyl, halo, haloalkyl, alkoxy, hydroxyalkyl,alkoxyalkyl, hydroxy, cyano, or oxo;

ring D is phenyl or a 5 or 6 membered heteroaryl ring which, including Xand X¹, contains one to three heteroatoms independently selected from N,O, or S and ring D can optionally be substituted with alkyl;

X and X¹ are independently N or C provided only one of X and X¹ can beN;

R³ is amino or aminoalkyl;

R⁴ is alkyl, cycloalkylalkyl, halo, hydroxy, amino, alkoxycarbonyl,hydroxyalkyl, alkoxyalkyl, 5 or 6 membered heteroaryl, or 4 to 6membered heterocyclyl wherein heteroaryl or heterocyclyl is substitutedwith R^(i) and/or R^(j) independently selected from hydrogen, alkyl,halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, cyano, alkylsulfoxide, oralkylsulfonyl; or

R³ and R⁴ together with the carbon atom to which they are attached forma ring of formula (c):

wherein:

m1 is 0, 1; or 2;

n1 is 0, 1, or 2; provided m1+n1 is 1, 2, or 3;

one of Y and Z is CH₂, O, S, SO, SO₂, or NH; and the other of X and Y isCH₂; and wherein ring of formula (c) is substituted with R^(n) and/orR^(o) independently selected from hydrogen, alkyl, halo, haloalkyl,haloalkoxy, alkoxy, hydroxy, cyano, alkylsulfoxide, alkylsulfonyl, oroxo; or

a pharmaceutically acceptable salt thereof.

42. In embodiment 42, the compound of any one of embodiments 37 to 41,or a pharmaceutically acceptable salt thereof has the structure offormula (III′)

43. In embodiment 43, the compound of any one of embodiments 37 to 41,or a pharmaceutically acceptable salt thereof has the structure offormula (IV′):

44. In embodiment 44, the compound of any one of embodiments 37 to 41,or a pharmaceutically acceptable salt thereof has the structure offormula (V′) or (VI′):

In one sub-embodiment of embodiment 4, the compound or apharmaceutically acceptable salt thereof has structure (V). In anothersub-embodiment of embodiment 4, the compound or a pharmaceuticallyacceptable salt thereof has structure (VI).

45. In embodiment 45, the compound of any one of embodiments 37 to 43and sub-embodiments contained therein, or a pharmaceutically acceptablesalt thereof is wherein R¹ is hydrogen.

46. In embodiment 46, the compound of any one of embodiments 37 to 43and sub-embodiment contained therein, or a pharmaceutically acceptablesalt thereof is wherein R¹ is deuterium.

47. In embodiment 7, the compound of any one of embodiments 37 to 46 andsub-embodiments contained therein, or a pharmaceutically acceptable saltthereof is wherein L is S.

48. In embodiment 8, the compound of any one of embodiments 37 to 46 andsub-embodiments contained therein, or a pharmaceutically acceptable saltthereof is wherein L is S(O) or S(O)₂.

49. In embodiment 49, the compound of any one of embodiments 37 to 46and sub-embodiments contained therein, or a pharmaceutically acceptablesalt thereof is wherein L is bond.

50. In embodiment 50, the compound of any one of embodiments 37 to 46and sub-embodiments contained therein, or a pharmaceutically acceptablesalt thereof is wherein L is CR⁵R⁶ where R⁵ and R⁶ are independentlyhydrogen or alkyl. In one sub-embodiment, of embodiment 50, L is CH₂. Inanother sub-embodiment of embodiment 50, L is C(CH₃)₂.

51. In embodiment 11, the compound of any one of embodiments 37 to 50and sub-embodiments contained therein, or a pharmaceutically acceptablesalt thereof is wherein R² is hydroxyalkyl. In a first sub-embodiment ofembodiment 51, R² is hydroxymethyl.

52. In embodiment 52, the compound of any one of embodiments 37 to 50and sub-embodiments contained therein, or a pharmaceutically acceptablesalt thereof is wherein R² is alkylsulfonyl. In a first sub-embodimentof embodiment 52, R² is methylsulfonyl or ethylsulfonyl.

53. In embodiment 53, the compound of any one of embodiments 37 to 50and sub-embodiments contained therein, or a pharmaceutically acceptablesalt thereof is wherein R² is alkylsulfoxide. In a first sub-embodimentof embodiment 53, R² is methylsulfoxide, ethylsulfoxide, orisopropylsulfoxide. In a second sub-embodiment of embodiment 53, R² ismethylsulfoxide.

54. In embodiment 54, the compound of any one of embodiments 37 to 50and sub-embodiments contained therein, or a pharmaceutically acceptablesalt thereof is wherein R² is —CD₂OH.

55. In embodiment 55, the compound of any one of embodiments 37 to 50and sub-embodiments contained therein, or a pharmaceutically acceptablesalt thereof is wherein R² is alkoxycarbonyl, aminosulfonyl oraminocarbonyl. In a first sub-embodiment of embodiment 55, R² is—S(O)₂NH₂. In a second sub-embodiment of embodiment 55, R² is —CONH₂. Ina third sub-embodiment of embodiment 55, R² is —C(O)CH₃.

56. In embodiment 16, the compound of any one of embodiments 37 to 50and sub-embodiments contained therein, or a pharmaceutically acceptablesalt thereof is wherein R² is hydroxy.

57. In embodiment 57, the compound of any one of embodiments 37 to 50and sub-embodiments contained therein, or a pharmaceutically acceptablesalt thereof is wherein R² is halo. In a sub-embodiment of embodiment17, R² is chloro.

58. In embodiment 58, the compound of any one of embodiments 37 to 57and sub-embodiments contained therein, or a pharmaceutically acceptablesalt thereof is wherein:

is a ring of formula (a):

wherein:

m is 0, 1; or 2;

n is 0, 1, or 2 wherein when n is 2 then one of the CH₂ can be replacedwith O, S, or SO₂;

provided m+n is 1, 2, or 3;

k is 0, 1 or 2

z is 0, 1, or 2

each R^(d) is independently hydrogen, alkyl, or halogen;

R^(e) and R^(e1) are independently hydrogen, alkyl, halogen, haloalkyl,alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, cyano or oxo; or

when R^(e) and R^(e1) are attached to the same carbon atom, then R^(e)and R^(e1) together with the carbon atom to which they are attached formcycloalkylene or heterocyclylene.

In a first embodiment of embodiment 58,

is a ring of formula:

59. In embodiment 59, the compound of any one of embodiments 37 to 57and sub-embodiments contained therein, or a pharmaceutically acceptablesalt thereof is wherein:

is a ring of formula (a):

In a first sub-embodiment of embodiment 59,

In a second sub-embodiment of embodiment 59,

In a third sub-embodiment of embodiment 59,

60. In embodiment 60, the compound of any one of embodiments 37 to 57and sub-embodiments contained therein, or a pharmaceutically acceptablesalt thereof is wherein

preferably where z is 1, and

where R³ is amino or aminoalkyl; and

R⁴ is alkyl, cycloalkylalkyl, halo, hydroxy, amino, alkoxycarbonyl,hydroxyalkyl, alkoxyalkyl, 5 or 6 membered heteroaryl, or 4 to 6membered heterocyclyl wherein heteroaryl or heterocyclyl is substitutedwith R^(i) and/or R^(j) independently selected from hydrogen, alkyl,halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, cyano, alkylsulfoxide, oralkylsulfonyl. In a sub-embodiment of embodiment 20, z is 0, R³ isaminomethyl, and R⁴ is methyl.

61. In embodiment 61, the compound of any one of embodiments 37 to 57and sub-embodiments contained therein, or a pharmaceutically acceptablesalt thereof is wherein

preferably where z is 1, and

where R³ and R⁴ together with the carbon atom to which they are attachedform a ring of formula (c):

wherein:

m1 is 0, 1; or 2;

n1 is 0, 1, or 2; provided m1+n1 is 1, 2, or 3;

R^(k) and R^(m) are independently hydrogen, alkyl, or haloalkyl;

one of Y and Z is CH₂, O, S, S(O), S(O)₂, or NH; and the other of X andY is CH₂; and wherein ring of formula (c) is substituted with R^(n)and/or R^(o) independently selected from hydrogen, alkyl, alkyldienyl,alkenyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, cyano,alkylsulfoxide, alkylsulfonyl, oxo, cycloalkyl, heterocyclyl, andheteroaryl; or

when R^(n) and R^(o) are attached to the same carbon atom, then R^(n)and R^(o) together with the carbon atom to which they are attached formcycloalkylene or heterocyclylene;

In a first subembodiment of embodiment 61,

62. In embodiment 62, the compound of any one of embodiments 37 to 57and sub-embodiments contained therein, or a pharmaceutically acceptablesalt thereof is wherein

preferably where z is 1, and

where R³ and R⁴ together with the carbon atom to which they are attachedform a ring of formula (c):

wherein:

m1 is 0, 1; or 2;

n1 is 0, 1, or 2; provided m1+n1 is 1, 2, or 3;

R^(k) and R^(m) are independently hydrogen, alkyl, or haloalkyl;

one of Y and Z is CH₂, 0, S, S(O), S(O)₂, or NH; and the other of X andY is CH₂; and wherein ring of formula (c) is substituted with R^(n)and/or R^(o) independently selected from hydrogen, alkyl, alkyldienyl,alkenyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, cyano,alkylsulfoxide, alkylsulfonyl, oxo, cycloalkyl, heterocyclyl, andheteroaryl.

In a first sub-embodiment of embodiment 62,

In a second sub-embodiment of embodiment 62,

In a third sub-embodiment of embodiment 62,

In a fourth sub-embodiment of embodiment 62,

63. In embodiment 63, the compound of any one of embodiments 37 to 60and sub-embodiments contained therein, or a pharmaceutically acceptablesalt thereof R^(a) and R^(b) are independently selected from hydrogen,alkyl, amino, cycloalkyl, alkyldienyl, alkenyl, halo, haloalkyl, alkoxy,haloalkoxy, hydroxy, hydroxyalkyl, cyano, aminoalkyl, carboxy, andalkoxycarbonyl and R^(c) is hydrogen, alkyl, halo, hydroxy, alkoxy,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, —S(O)R, S(O)₂R, —C(O)R, —NR′C(O)R,—NR′SO₂R, —C(O)NR′R″, —S(O)₂NR′R″, —NR′R″, or —NR′C(O)C(O)R where R isalkyl, cycloalkyl, cycloalkylalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substituted heteroaryl, oroptionally substituted heteroaralkyl, and R′ and R″ are independentlyhydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cycloalkylalkyl,optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted heteroaryl, or optionally substitutedheteroaralkyl or R′ and R″ together with the nitrogen atom to which theyare attached form optionally substituted heterocyclyl; or

when R^(c) and R^(a) are attached to the same carbon of cycloalkyl orfused heteroaryl ring, then R^(e) and R^(a) together with the carbonatom to which they are attached form cycloalkylene or heterocyclylene.

In a first sub-embodiment of embodiment 63, R^(a) and R^(b) areindependently selected from hydrogen, alkyl, amino, cycloalkyl,alkyldienyl, alkenyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, andcyano and R^(e) is hydrogen or —NR′R″ where R′ and R″ are independentlyhydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, or optionallysubstituted heterocyclyl.

In a second sub-embodiment of embodiment 63, R^(a) and R^(b) areindependently selected from hydrogen, alkyl, halo, haloalkyl, alkoxy,haloalkoxy, hydroxy, and cyano and R^(e) is hydrogen or —NR′R″ where R′and R″ are independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl,aminoalkyl, or optionally substituted heterocyclyl.

In a third sub-embodiment of embodiment 63, R^(a) and R^(b) areindependently selected from hydrogen, alkyl, halo, haloalkyl, alkoxy,haloalkoxy, hydroxy, and cyano and R^(c) is hydrogen or —NR′R″ where R′and R″ are independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl,aminoalkyl, or optionally substituted heterocyclyl.

In a fourth sub-embodiment of embodiment 63, R^(a) and R^(b) areindependently selected from hydrogen, methyl, ethyl, methoxy, ethoxy,chloro, fluoro, difluoromethyl, trifluoromethyl, difluoromethoxy,trifluoromethoxy, hydroxy, or cyano, and R^(c) is hydrogen.

In a fifth sub-embodiment of embodiment 63, and first subembodimenttherein, ring A has the structure (d):

where:

t is 0, 1 or 2;

ring E is 4 to 7 membered heterocycle containing 1 or 2 heteroatomsindependently selected from O, N, S, and SO₂ where the remaining atomsare carbon; and W is O, CH₂, or N; substituted wilt R^(a), R^(b), and/orR^(c) wherein R^(a) and R^(b) are independently selected from hydrogen,amino, alkyl, alkyldienyl, alkenyl, halo, haloalkyl, alkoxy, haloalkoxy,hydroxy, hydroxyalkyl, cyano, aminoalkyl, carboxy, and alkoxycarbonyland R^(c) is hydrogen, alkyl, halo, hydroxy, or alkoxy; or

when R^(a) and R^(c) are attached to the same carbon atom, R^(a) andR^(c) together together with the carbon atom to which they are attachedform cycloalkylene or heterocyclylene.

In a first embodiment, of the fifth sub-embodiment, ring A is

In a second embodiment, of the fourth sub-embodiment, ring A is:

In a second embodiment of the fifth sub-embodiment, ring A is:

In an sixth subembodiment of embodiment 63, ring A is

It is understood that the embodiments 37 to 63 set forth above includeall combination of embodiments and subembodiments listed therein. Forexample, the ring A listed in fifth subembodiment of embodiment 63, canindependently be combined with one or more of the embodiments 35 to 62and/or subembodiments contained therein.

66. A compound of Formula (I):

wherein:

A and E are independently selected from a bond, CH₂, O, NH, S, andS(O)₂;

Z is hydrogen, alkyl, halo, haloalkyl, haloalkoxy, cyano, cycloalkyl,heterocyclyl, heteroaryl (wherein cycloalkyl, heterocyclyl, andheteroaryl are optionally substituted with one to three halo),—O(alk)_(y)R^(a), —O(alk)OR^(b), —S(O)R^(c), —S(O)₂R^(d),—NR^(e)C(O)R^(f), —NR^(g)SO₂R^(h), —OC(O)NR^(i)R^(j), —C(O)NR^(k)R^(m),—S(O)₂NR^(k)R^(m), —NR^(p)R^(q), —NR^(r)C(O)C(O)R^(s) or -Y-M (wherein Yis bond, O, or SO₂ and M is alkyl, haloalkyl, cycloalkyl, heterocyclyl,or heteroaryl wherein alkyl, haloalkyl, cycloalkyl, heterocyclyl andheteroaryl are substituted with —O(alk)_(y)R^(a), —O(alk)OR^(b),—S(O)R^(c), —S(O)₂R^(d), —NR^(e)C(O)R^(f), —NR^(g)SO₂R^(h),—OC(O)NR^(i)R^(j), —C(O)NR^(k)R^(m), —S(O)₂NR^(n)R^(o), —NR^(p)R^(q), or—NR^(r)C(O)C(O)R^(s) and cycloalkyl, heterocyclyl, and heteroaryl areoptionally further substituted with 1 to 3 halo); wherein each y is 0 or1, each alk is alkylene, and each R^(c), R^(d), R^(f), R^(h), and R^(s)are independently alkyl, cycloalkyl, cycloalkylalkyl, optionallysubstituted heterocyclyl, optionally substituted heterocyclylalkyl,optionally substituted aryl, optionally substituted aralkyl, optionallysubstituted heteroaryl, or optionally substituted heteroaralkyl; andeach R^(a), R^(b), R^(e), R^(g), R^(i), Rj, R^(k), R^(m), R^(n), R^(o),R^(p), R^(q), R^(r), and R^(s) are independently hydrogen, alkyl,cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted heteroaryl, or optionally substitutedheteroaralkyl; or, independently of each other, each R^(i) and R^(j),R^(k) and R^(m), R^(n) and R^(o), and R^(p) and R^(q), together with thenitrogen atom to which they are attached form optionally substitutedheterocyclyl;

R¹, R², R³, and R⁴ are independently selected from hydrogen, alkyl,cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, cyano, hydroxy,hydroxylalkyl, amino, and aminoalkyl;

or one of R¹ and R² and R³ and R⁴, when attached to the same carbon,combine to form oxo, alkyldienyl, 3 to 6 membered cycloalkylene, or 4 to6 membered optionally substituted heterocyclylene;

R⁵ and R⁶ are independently selected from hydrogen, alkyl, cycloalkyl,halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, cyano, hydroxylalkyl,amino, and aminoalkyl, or wherein one of R⁵ and R⁶ is optionallysubstituted heterocyclyl and the other R⁵ and R⁶ is selected fromhydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy,hydroxy, cyano, hydroxylalkyl, amino, and aminoalkyl;

L is bond, O, S, S(O), S(O)₂, or CR⁷R⁸ where R⁷ and R⁸ are independentlyhydrogen or alkyl;

Z¹ is a group of formula (a) or (b):

wherein:

R⁹ is hydrogen, alkyl, halo, hydroxy, amino, or haloalkyl;

R¹⁰ is hydrogen, alkyl, halo, hydroxy, hydroxyalkyl, —CD₂OH,alkylsulfoxide, alkylsulfonyl, amino, aminoalkyl, aminosulfonyl,aminocarbonyl, carboxy, cyano, or alkoxycarbonyl;

R¹³ is hydrogen, alkyl, halo, hydroxy, amino, or haloalkyl;

R¹⁴ is hydrogen, alkyl, or haloalkyl;

R¹¹ and R¹⁵ are selected from amino and aminoalkyl;

R¹² and R¹⁶ are selected from hydrogen, cyano, halo, alkyl, haloalkyl,alkoxy, haloalkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl,where alkyl, cycloalkyl, aryl, heterocyclyl and heteroaryl areoptionally substituted with one to three substituents independentlyselected from alkyl, halo, haloalkyl, haloalkoxy, alkoxy, and cyano;

or R¹¹ and R¹², and R¹⁵ and R¹⁶ together with the carbon atom to whichthey are attached form a ring of formula (c):

wherein:

e is 0, 1; or 2;

k is 0, 1, or 2 provided e+k is 1, 2, or 3;

q is 0, 1, or 2, or 3;

R¹⁷ and R¹⁸ are independently selected from hydrogen, alkyl, cycloalkyland haloalkyl;

each R¹⁹ is independently selected from hydrogen, alkyl, halo,haloalkyl, haloalkoxy, alkoxy, hydroxy, cyano, alkylsulfoxide,alkylsulfonyl, oxo, cycloalkyl, optionally substituted heterocyclyl, andoptionally substituted heteroaryl; or

when two R¹⁹ groups are attached to the same carbon atom, the two R¹⁹groups together with the carbon atom to which they are attached formcycloalkylene or heterocyclylene.

ring D is absent or present; wherein:

-   -   (i) when ring D is absent, then one of Q and W is CH₂, O, S,        S(O), S(O)₂, or NH; and the other of Q and W is CH₂; and    -   (ii) when ring D is present, then Q and W are independently N or        C provided only one of Q and W is N; and ring D is phenyl or a 5        or 6 membered heteroaryl ring which, including Q and W, contains        one to three heteroatoms independently selected from N, O, and S        and ring D is optionally be substituted with one or two        substituents independently selected from alkyl, cycloalkyl,        halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl,        cyano, amino, aminoalkyl, carboxy, and optionally substituted        heterocyclyl; or a pharmaceutically acceptable salt thereof.

67. The compound of embodiment 66, or a pharmaceutically acceptable saltthereof is wherein the compound has a structure of formula (II)

68. The compound of embodiment 67 or 68, and or a pharmaceuticallyacceptable salt thereof is wherein the compound has a structure ofFormula (IIA)

69. The compound of embodiment 66, or a pharmaceutically acceptable saltthereof is wherein the compound has a structure of formula (III):

70. The compound of embodiment 66 or 69, or a pharmaceuticallyacceptable salt thereof is wherein the compound has structure of Formula(IIA):

71. The compound of any one of embodiments 66 to 70, or apharmaceutically acceptable salt thereof wherein E is O and A is CH₂ orbond.

72. The compound of any one of embodiments 66 to 70, or apharmaceutically acceptable salt thereof wherein E is O and A is bond.

73. The compound of embodiment 68, or a pharmaceutically acceptable saltthereof has a structure of formula (IIB):

74. The compound of embodiment 70, or a pharmaceutically acceptable saltthereof has the structure of formula (IIIB):

75. The compound of any one of embodiments 66 to 74, or apharmaceutically acceptable salt thereof wherein Z is hydrogen, alkyl,halo, haloalkyl, haloalkoxy, cyano, cycloalkyl, heterocyclyl, heteroaryl(wherein cycloalkyl, heterocyclyl, and heteroaryl are optionallysubstituted with one to three halo), —O(alk)_(y)R^(a), —O(alk)OR^(b),—S(O)₂R^(d), —OC(O)NR^(i)R^(j), —S(O)₂NR^(n)R^(o), —NR^(p)R^(q), or -Y-M(wherein Y is bond, O, or SO₂ and M is alkyl, haloalkyl, cycloalkyl,heterocyclyl, or heteroaryl wherein alkyl, haloalkyl, cycloalkyl,heterocyclyl and heteroaryl are substituted with —O(alk)_(y)R^(a),—O(alk)OR^(b), —S(O)₂R^(d), or —NR^(p)R^(q) and cycloalkyl,heterocyclyl, and heteroaryl are optionally further substituted with 1to 3 halo).

76. The compound of any one of embodiments 66 to 74, or apharmaceutically acceptable salt thereof wherein Z is -Y-M (wherein Y isbond or O and M is alkyl, haloalkyl, cycloalkyl, heterocyclyl, orheteroaryl wherein alkyl, haloalkyl, cycloalkyl, heterocyclyl andheteroaryl are substituted with —O(alk)OR^(b), —S(O)₂R^(d),—NReC(O)R^(f), —NR^(g)SO₂R^(h), —OC(O)NR^(i)R^(j), —C(O)NR^(k)R^(m), or—S(O)₂NR^(o)R^(p).

77. The compound of any one of embodiments 66 to 74, or apharmaceutically acceptable salt thereof wherein Z is -Y-M (wherein Y isbond and M is alkyl, haloalkyl, cycloalkyl, heterocyclyl, or heteroarylwherein alkyl, haloalkyl, cycloalkyl, heterocyclyl and heteroaryl aresubstituted with —O—R^(a) where R^(a) is alkyl, cycloalkyl,cycloalkylalkyl, aminoalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substituted aryl,or optionally substituted heteroaryl.

78. The compound of any one of embodiments 66 to 74, or apharmaceutically acceptable salt thereof wherein Z is -Y-M (wherein Y isbond and M is alkyl, haloalkyl, cycloalkyl, heterocyclyl, or heteroarylwherein alkyl, haloalkyl, cycloalkyl, heterocyclyl and heteroaryl aresubstituted with —O(alk)OR⁹ where R^(a) is alkyl, cycloalkyl,cycloalkylalkyl, aminoalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substituted aryl,or optionally substituted heteroaryl.

79. The compound of any one of embodiments 66 to 74, or apharmaceutically acceptable salt thereof wherein Z is —OR^(a) whereR^(a) is alkyl, cycloalkyl, cycloalkylalkyl, aminoalkyl, optionallysubstituted heterocyclyl, optionally substituted heterocyclylalkyl,optionally substituted aryl, or optionally substituted heteroaryl.

80. The compound of any one of embodiments 66 to 74, or apharmaceutically acceptable salt thereof wherein Z is —O(alk)OR^(b)where R^(b) is alkyl, cycloalkyl, cycloalkylalkyl, aminoalkyl,optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted aryl, or optionallysubstituted heteroaryl.

81. The compound of any one of embodiments 66 to 74, or apharmaceutically acceptable salt thereof wherein Z is hydrogen, fluoro,cyano, methoxy, hydroxy, cyclopentyloxy, tetrahydrofuran-3-yloxy,oxetan-3-yloxy, methoxymethyloxy, methoxyethyloxy, methylsulfonyl,aminocarbonyloxy, pyrazol-1-yl, hydroxymethyl, methoxymethyl,ethoxymethyl, methoxymethyloxymethyl, ethoxymethyloxymethyl,methoxyethyloxymethyl, cyclopropylmethyloxy, oroxetan-3-ylmethyloxymethyL

82. The compound of any one of embodiments 66 to 74, or apharmaceutically acceptable salt thereof wherein Z is methoxymethyloxy,methoxyethyloxy, methoxymethyl, methoxymethyloxymethyl,ethoxymethyloxymethyl, methoxyethyloxymethyl, cyclopropylmethyloxy, oroxetan-3-ylmethyloxymethyL

83. The compound of any one of embodiments 66 to 74, or apharmaceutically acceptable salt thereof wherein Z is methoxymethyl,methoxymethyloxymethyl, ethoxymethyloxymethyl, methoxyethyloxymethyl,cyclopropylmethyloxymethyl, or oxetan-3-ylmethyloxymethyl.

84. The compound of any one of embodiments 66 to 74, or apharmaceutically acceptable salt thereof wherein Z is fluoro.

85. The compound of any one of embodiments 66 to 84, or apharmaceutically acceptable salt thereof wherein R⁹ and R¹³ arehydrogen.

86. The compound of any one of embodiments 66 to 84, or apharmaceutically acceptable salt thereof wherein R⁹ and R¹³ are amino.

87. The compound of any one of embodiments 66 to 84, or apharmaceutically acceptable salt thereof wherein R⁹ and R¹³ are amino.

88. The compound of any one of embodiments 66 to 84, or apharmaceutically acceptable salt thereof wherein R⁹ and R¹³ are methyl.

89. The compound of any one of embodiments 66 to 84, or apharmaceutically acceptable salt thereof wherein R⁹ and R³ areindependently hydrogen, alkyl, or amino.

90. The compound of any one of embodiments 66 to 89, or apharmaceutically acceptable salt thereof wherein L is S.

91. The compound of any one of embodiments 66 to 89, or apharmaceutically acceptable salt thereof wherein L is S(O) or S(O)₂.

92. The compound of any one of embodiments 66 to 89, or apharmaceutically acceptable salt thereof wherein L is bond.

93. The compound of any one of embodiments 66 to 89, or apharmaceutically acceptable salt thereof wherein L is CR⁷R⁸ where R⁵ andR⁶ are independently hydrogen or alkyl.

94. The compound of any one of embodiments 66 to 68, 71 to 73 and 75 to93, or a pharmaceutically acceptable salt thereof wherein R¹⁰ ishydroxyalkyl.

95. The compound of any one of embodiments 66 to 68, 71 to 73 and 75 to93, or a pharmaceutically acceptable salt thereof wherein R¹⁰ ishydroxymethyl.

96. The compound of any one of embodiments 66, 69 to 72, and 74 to 93,or a pharmaceutically acceptable salt thereof is wherein R¹⁴ is hydrogenor methyl.

97. The compound of any one of embodiments 66 to 96, or apharmaceutically acceptable salt thereof wherein:

R¹¹ and R¹⁵ are selected from amino and aminoalkyl; and R¹² and R¹⁶ areindependently selected from hydrogen, cyano, halo, alkyl, haloalkyl,alkoxy, haloalkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl,where alkyl, cycloalkyl, aryl, heterocyclyl and heteroaryl areoptionally substituted with one to three substituents independentlyselected from alkyl, halo, haloalkyl, haloalkoxy, alkoxy, and cyano.

98. The compound of embodiments 97, or a pharmaceutically acceptablesalt thereof wherein R¹¹ and R¹⁵ are aminomethyl and R¹² and R¹⁶ aremethyl.

99. The compound of any one of embodiments 66 to 96, or apharmaceutically acceptable salt thereof wherein R¹¹ and R¹², and R¹⁵and R¹⁶ together with the carbon atom to which they are attached form aring of formula (c):

100. The compound of embodiment 99, or a pharmaceutically acceptablesalt thereof wherein ring of formula (c) is:

101. The compound of any one of embodiments 66 to 96, or apharmaceutically acceptable salt thereof wherein R¹¹ and R¹², and R¹⁵and R¹⁶ together with the carbon atom to which they are attached form aring of formula (c):

102. The compound of embodiment 101, or a pharmaceutically acceptablesalt thereof wherein ring of formula (c) is:

103. The compound of any one of embodiments 66 to 102, or apharmaceutically acceptable salt thereof wherein R¹, R², R³, and R⁴ areindependently selected from hydrogen, alkyl, halo, haloalkyl,haloalkoxy, alkoxy, cyano, and hydroxy, amino.

104. The compound of embodiment 103, or a pharmaceutically acceptablesalt thereof wherein R¹, R², R³, and R⁴ is hydrogen and the remainingthree of R¹, R², R³, and R⁴ are independently selected from hydrogen,methyl, fluoro, methoxy, hydroxy, and amino.

105. The compound of embodiment 103, or a pharmaceutically acceptablesalt thereof wherein R¹, R², R³, and R⁴ are hydrogen.

106. The compound of any one of embodiments 66 to 105, or apharmaceutically acceptable salt wherein R^(S) is hydrogen, alkyl, halo,or amino and R⁶ is hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy,hydroxy, or cyano.

107. The compound of embodiment 106, or a pharmaceutically acceptablesalt thereof wherein R⁵ and R⁶ are hydrogen.

108. A pharmaceutical composition comprising a compound, or apharmaceutically acceptable salt thereof, of any one of embodiments 66to 107 and a pharmaceutically acceptable excipient.

109. A method of treating a disease treatable by inhibition of SHP2 in apatient which method comprises administering to the patient, preferablya patient in need of such treatment, a therapeutically effective amountof a compound, or a pharmaceutically acceptable salt thereof, ofany oneof embodiments 66 to 107 or which method comprises administering to thepatient, preferably a patient in need of such treatment, apharmaceutical composition comprising a compound, or a pharmaceuticallyacceptable salt thereof, of any one of embodiments 66 to 107 and apharmaceutically acceptable excipient.

110. The method of embodiment 109 wherein the disease is cancer.

111. The method of embodiment 110 wherein the cancer is selected fromlung, stomach, liver, colon, kidney, breast, pancreatitis, juvenilemyelomonocytic leukemias, neurolastoma, melanoma, and acute myeloidleukemia.

112. The method of embodiment 109 wherein the disease is selected fromNoonan syndrome and Leopard syndrome.

General Synthetic Scheme

Compounds of this disclosure can be made by the methods depicted in thereaction schemes shown below.

The starting materials and reagents used in preparing these compoundsare either available from commercial suppliers such as Aldrich ChemicalCo., (Milwaukee, Wis.), Bachem (Torrance, Calif.), or Sigma (St. Louis,Mo.) or are prepared by methods known to those skilled in the artfollowing procedures set forth in references such as Fieser and Fieser'sReagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons,1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 andSupplementals (Elsevier Science Publishers, 1989); Organic Reactions,Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced OrganicChemistry, (John Wiley and Sons, 4th Edition) and Larock's ComprehensiveOrganic Transformations (VCH Publishers Inc., 1989). These schemes aremerely illustrative of some methods by which the compounds of thisdisclosure can be synthesized, and various modifications to theseschemes can be made and will be suggested to one skilled in the artreading this disclosure. The starting materials and the intermediates,and the final products of the reaction may be isolated and purified ifdesired using conventional techniques, including but not limited tofiltration, distillation, crystallization, chromatography and the like.Such materials may be characterized using conventional means, includingphysical constants and spectral data.

Unless specified to the contrary, the reactions described herein takeplace at atmospheric pressure over a temperature range from about −78°C. to about 150° C., such as from about 0° C. to about 125° C. andfurther such as at about room (or ambient) temperature, e.g., about 20°C.

General Synthetic Scheme

Compounds of Formula (I), (IA), (IB), or (IC) in which, L is S and othergroups are as defined in Summary can be prepared as illustrated anddescribed in Scheme 1 below.

Coupling of a compound of formula 1-a, where X¹ is halogen, where Z, R¹,R², R³, R⁴, R⁵, and R⁶ are as defined in the Summary or a precursorgroup thereof and E and Aare as defined in the Summary, with a compoundof formula 1-d where M¹ is metal such as sodium or potassium, in thepresence of transition metal catalyst such as Pd₂(dba)₃ and xantphosunder standard coupling condition provides compounds of Formula (I). Ifa compound of formula 1-a is substituted with an amino group, then theamino group can be protected with a suitable protecting group such ast-butyl carbamate prior to the coupling reaction. Removal of the aminoprotecting group by methods well known in the art then provides acompound of Formula (I), (IA), (IB), or (IC)

Alternatively, compounds of Formula (I), (IA), (IB), or (IC) can beprepared by reacting compound of formula 1-a with 3-mercaptopropanoateester in the presence of transition metal catalyst such as Pd₂(dba)₃ andxantphos under standard coupling condition to provide a compound offormula 1-b where R′ is an alkyl group such as 3-methylheptane.Treatment of a compound of formla 1-b with abase such as potassiumt-butoxide, sodium t-butoxide, sodium methoxide, and the like, providescompound of formula 1-c as a thiosalt, where M⁺ is a metal ion such aspotassium or sodium. Coupling of 1-c with a compound of formula 1-e orformula 1-f where X² or X³ is halo provides a compound of Formula (I),(IA), (IB), or (IC) where Z1 is a group of formula (a) or (b),respectively.

Compounds of formula 1-a where X¹ is halogen, E is O, and A, E, Z, R¹,R², R³, R⁴, R⁵, R⁶, are as defined in Summary or a precursor groupthereof, can be prepared as illustrated and described in Methods 1 and 2below.

Method (1):

Coupling a compound of formula 2-b in which R³ and R⁶ are as defined inSummary or a precursor group thereof with an alcohol of formula 2-awhere PG is a suitable amino protecting group such as Boc, underMitsunobu condition, for example, using diethyl azodicarboxylate andtriphenyl phosphine provides a compound of formula 2-c. Compounds offormula 2-b are commercially available or they can be prepared bymethods well known in the art. For example, 2-fluoropyridin-3-ol iscommercially available. Compounds of formula 2-a are commerciallyavailable or they can be prepared by methods well known in the art. Forexample, tert-butyl (S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate,tert-butyl(R)-2-(hydroxymethyl)pyrrolidin-1-carboxylate,tert-butyl(2S,4S)-4-fluoro-2-(hydroxymethyl)-pyrrolidine-1-carboxylate,tert-butyl (2S,4R)-4-fluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate,tert butyl(S)-4,4-difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate,tert-butyl(2S,4R)-2-(hydroxymethyl)-4-methoxypyrrolidine-1-carboxylate,tert-butyl(2S,4S)-2-(hydroxymethyl)-4-methoxypyrrolidine-1-carboxylate,tert-butyl (S)-6-(hydroxymethyl)-5-azaspiro[2.4]heptane-5-carboxylate,tert-butyl (R)-3-(hydroxymethyl)morpholino-4-carboxylate, tert-butyl(S)-3-(hydroxymethyl)morpholine-4-carboxylate, tert-butyl(R)-2-(hydroxymethyl)azetidine-1-carboxylate, tert-butyl(S)-2-(hydroxymethyl)azetidine-1-carboxylate are commercially available.

Removal of the amino protecting group provides a compound of formula2-d. For example, Boc group can be cleaved under acidic condition suchHCl in dioxane. Cyclization of compound 2-d with a base such as K₂CO₃,sodium carbonate, and the like, provides a compound of formula 2-e.Lithiation of compound 2-e using alkyl lithium such n-BuLi, followed bytrapping with iodine provides a compound of formula 1-a.

Method (2)

Alternatively, coupling a compound of formula 3-a where X¹ is halogen,R⁵ and R⁶ areas defined in summary and an alcohol of formula 2-a wherePG is an amino protecting group such as Boc, under Mitsunobu condition,for example, using diethyl azodicarboxylate and triphenyl phosphineprovides a compound of formula 3-b. Compounds of formula 3-a arecommercially available or they can be prepared by methods well known inthe art. For example, 2-fluoro-4-iodopyridin-3-ol is commerciallyavailable. Compound 3-c is converted to a compound of formula 1-a asdescribed in Scheme 1 above.

Utility

The Src Homology-2 phosphatase (SHP2) is a protein tyrosine phosphataseencoded by the PTPN1 1 gene that contributes to multiple cellularfunctions including proliferation, differentiation, cell cyclemaintenance and migration. SHP2 is involved in signaling through theRas-mitogen-activated protein kinase, the JAK-STAT or thephosphoinositol 3-kinase-AKT pathways. SHP2 mediates activation of Erk1and Erk2 (Erk1/2, Erk) MAP kinases by receptor tyrosine kinases such asErbB1, ErbB2 and c-Met.

SHP2 has two N-terminal Src homology 2 domains (N-SH2 and C-SH2), acatalytic domain (PTP), and a C-terminal tail. The two SH2 domainscontrol the subcellular localization and functional regulation of SHP2.The molecule exists in an inactive conformation, inhibiting its ownactivity via a binding network involving residues from both the N-SH2and PTP domains. In response to growth factor stimulation, SHP2 binds tospecific tyrosine-phosphorylated sites on docking proteins such as Gab1and Gab2 via its SH2 domains. This induces a conformational change thatresults in SHP2 activation.

Mutations in PTPN1l have been identified in several human diseases, suchas Noonan Syndrome, Leopard Syndrome, juvenile myelomonocytic leukemias,neuroblastoma, melanoma, acute myeloid leukemia and cancers of thebreast, lung and colon. SHP2 is an important downstream signalingmolecule for a variety of receptor tyrosine kinases, including thereceptors of platelet-derived growth factor (PDGF-R), fibroblast growthfactor (FGF-R) and epidermal growth factor (EGF-R). SHP2 is also animportant downstream signaling molecule for the activation of themitogen activated protein (MAP) kinase pathway which can lead to celltransformation, a prerequisite for the development of cancer. Knock-downof SHP2 significantly inhibited cell growth of lung cancer cell lineswith SHP2 mutation or EML4/ALK translocations as well as EGFR amplifiedbreast cancers and esophageal cancers. SHP2 is also activated downstreamof oncogenes in gastric carcinoma, anaplastic large-cell lymphoma andglioblastoma.

Noonan Syndrome (NS) and Leopard Syndrome (LS): PTPN11 mutations causeLS (multiple lentigenes, electrocardiographic conduction abnormalities,ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardationof growth, sensorineural deafness) and NS (congenital anomaliesincluding cardiac defects, craniofacial abnormalities and shortstature). Both disorders are part of a family of autosomal dominantsyndromes caused by germline mutations in components of theRAS/RAF/MEK/ERK mitogen activating protein kinase pathway, required fornormal cell growth and differentiation. Aberrant regulation of thispathway has profound effects, particularly on cardiac development,resulting in various abnormalities, including valvuloseptal defectsand/or hypertrophic cardiomyopathy (HCM). Perturbations of the MAPKsignaling pathway have been established as central to these disordersand several candidate genes along this pathway have been identified inhumans, including mutations in KRAS, NRAS, SOS1, RAF1, BRAF, MEK1, MEK2,SHOC2, and CBL. The gene most commonly mutated in NS and LS is PTPN1 1.Germline mutations in PTPN1 1 (SHP2) are found in −50% of the cases withNS and nearly all patients with LS that shares certain features with NS.For NS, Y62D and Y63C substitutions in the protein are largely invariantand are among the most common mutations. Both these mutations affect thecatalytically inactive conformation of SHP2 without perturbing thebinding of the phosphatase to its phosphorylated signaling partners.

Juvenile Myelomonocytic Leukemias (JMML):—Somatic mutations in PTPN1 1(SHP2) occur in about 35% of the patients with JMML, a childhoodmyeloproliferative disorder (MPD). These gain-of-function mutations aretypically point mutations in the N-SH2 domain or in the phosphatasedomain, which prevent self-inhibition between the catalytic domain andthe N-SH2 domain, resulting in SHP2 activity.

Acute Myeloid Leukemia: PTPN1 1 mutations have been identified in: −10%of pediatric acute leukemias, such as myelodysplastic syndrome (MDS);−7% of B cell acute lymphoblastic leukemia (B-ALL); and −4% of acutemyeloid leukemia (AML).

NS and leukemia mutations cause changes in amino acids located at theinterface formed by the N-SH2 and PTP domains in the self-inhibited SHP2conformation, disrupting the inhibitory intramolecular interaction,leading to hyperactivity of the catalytic domain.

SHP2 acts as a positive regulator in receptor tyrosine kinase (RTK)signaling. Cancers containing RTK alterations (EGFR amp, Her2 amp, FGFRamp, Met 31″15, translocated/activated RTK, i.e. ALK, BCR/ABL) includeEsophageal, Breast, Lung, Colon, Gastric, Glioma, Head and Neck cancers.

Esophageal cancer (or oesophageal cancer) is a malignancy of theesophagus. There are various subtypes, primarily squamous cell cancer(<50%) and adenocarcinoma. There is a high rate of RTK expression inesophageal adenocarcinoma and squamous cell cancer. A SHP2 inhibitor ofthe invention can, therefore, be employed for innovative treatmentstrategies.

Breast cancer is a major type of cancer and a leading cause of death inwomen, where patients develop resistance to current drugs. There arefour major subtypes of breast cancers including luminal A, luminal B,Her2 like, and triple negative/Basal-like. Triple negative breast cancer(TNBC) is an aggressive breast cancer lacking specific targeted therapy.Epidermal growth factor receptor I (EGFR) has emerged as a promisingtarget in TNBC. Inhibition of Her2 as well as EGFR via SHP2 may be apromising therapy in breast cancer.

Lung Cancer—NSCLC is currently a major cause of cancer-relatedmortality, accounting for about 85% of lung cancers (predominantlyadenocarcinomas and squamous cell carcinomas). Although cytotoxicchemotherapy remains an important part of treatment, targeted therapiesbased on genetic alterations such as EGFR and AIX in the tumor are morelikely to benefit from a targeted therapy.

Colon Cancer—Approximately 30% to 50% of colorectal tumors are known tohave a mutated (abnormal) KRAS, and BRAF mutations occur in 10 to 15% ofcolorectal cancers. For a subset of patients whose colorectal tumorshave been demonstrated to over express EGFR, these patients exhibit afavorable clinical response to anti-EGFR therapy.

Gastric Cancer is one of the most prevalent cancer types. Aberrantexpression of tyrosine kinases, as reflected by the aberrant tyrosinephosphorylation in gastric cancer cells, is known in the art. Threereceptor-tyrosine kinases, c-met (HGF receptor), FGF receptor 2, anderbB2/neu are frequently amplified in gastric carcinomas. Thus,subversion of different signal pathways may contribute to theprogression of different types of gastric cancers.

Neuroblastoma is a pediatric tumor of the developing sympathetic nervoussystem, accounting for about 8% of childhood cancers. Genomicalterations of the anaplastic lymphoma kinase (ALK) gene have beenpostulated to contribute to neuroblastoma pathogenesis.

Squamous-cell carcinoma of the head and neck (SCCHN). High levels ofEGFR expression are correlated with poor prognosis and resistance toradiation therapy in a variety of cancers, mostly in squamous-cellcarcinoma of the head and neck (SCCHN). Blocking of the EGFR signalingresults in inhibition of the stimulation of the receptor, cellproliferation, and reduced invasiveness and metastases. The EGFR is,therefore, a prime target for new anticancer therapy in SCCHN.

The present invention relates to compounds capable of inhibiting theactivity of SHP2. The invention further provides a process for thepreparation of compounds of the invention and pharmaceuticalpreparations comprising such compounds. Another aspect of the presentinvention relates to a method of treating SHP2-mediated disorderscomprising the step of administering to a patient in need thereof atherapeutically effective amount of a compound of formula I as definedin the Summary.

In certain embodiments, the present invention relates to theaforementioned method, wherein said SHP2-mediated disorders are cancersselected from, but not limited to: JMML; AML; MDS; B-ALL; neuroblastoma;esophageal; breast cancer, lung cancer; colon cancer; Gastric cancer,Head and Neck cancer.

The compounds of the present invention may also be useful in thetreatment of other diseases or conditions related to the aberrantactivity of SHP2. Thus, as a further aspect, the invention relates to amethod of treatment of a disorder selected from: NS; LS; JMML; AML; MDS;B-ALL; neuroblastoma; esophageal; breast cancer, lung cancer; coloncancer, gastric cancer; head and neck cancer.

A SHP2 inhibitor of the present invention may be usefully combined withanother pharmacologically active compound, or with two or more otherpharmacologically active compounds, particularly in the treatment ofcancer. For example, a compound of the current invention or apharmaceutically acceptable salt thereof, as defined above, may beadministered simultaneously, sequentially or separately in combinationwith one or more agents selected from chemotherapy agents, for example,mitotic inhibitors such as a taxane, a vinca alkaloid, paclitaxel,docetaxel, vincristine, vinblastine, vinorelbine or vinflunine, andother anticancer agents, e.g. cisplatin, 5-fluorouracil or5-fluoro-2-4(1H,3H)-pyrimidinedione (5FU), flutamide or gemcitabine.Such combinations may offer significant advantages, includingsynergistic activity, in therapy.

In certain embodiments, the present invention relates to theaforementioned method, wherein said compound is administeredparenterally.

In certain embodiments, the present invention relates to theaforementioned method, wherein said compound is administeredintramuscularly, intravenously, subcutaneously, orally, pulmonary,intrathecally, topically or intranasally.

In certain embodiments, the present invention relates to theaforementioned method, wherein said compound is administeredsystemically.

In certain embodiments, the present invention relates to theaforementioned method, wherein said patient is a mammal.

In certain embodiments, the present invention relates to theaforementioned method, wherein said patient is a primate.

In certain embodiments, the present invention relates to theaforementioned method, wherein said patient is a human.

In another aspect, the present invention relates to a method of treatingan SHP2-mediated disorder, comprising the step of: administering to apatient in need thereof a therapeutically effective amount of achemotherapeutic agent in combination with a therapeutically effectiveamount of a compound of formula I as defined in the Summary.

In addition to human cancer, inhibition of SHP2 also has the therapeuticpotential for treatment of systemic lupus erythematosus, rheumatoidarthritis and fibrosis.

Testing

The SHP2 inhibitory activity of the compounds of Formula (I), (IA),(IB), and (IC) can be tested using the in vitro assay described inBiological Examples 1 below.

Pharmaceutical Compostions

In general, the compounds of this disclosure will be administered in atherapeutically effective amount by any of the accepted modes ofadministration for agents that serve similar utilities. Therapeuticallyeffective amounts of compounds this disclosure may range from about 0.01to about 500 mg per kg patient body weight per day, which can beadministered in single or multiple doses. A suitable dosage level may befrom about 0.1 to about 250 mg/kg per day; about 0.5 to about 100 mg/kgper day. A suitable dosage level may be about 0.01 to about 250 mg/kgper day, about 0.05 to about 100 mg/kg per day, or about 0.1 to about 50mg/kg per day. Within this range the dosage can be about 0.05 to about0.5, about 0.5 to about 5 or about 5 to about 50 mg/kg per day. For oraladministration, the compositions can be provided in the form of tabletscontaining about 1.0 to about 1000 milligrams of the active ingredient,particularly about 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250,300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the activeingredient. The actual amount of the compound of this disclosure, i.e.,the active ingredient, will depend upon numerous factors such as theseverity of the disease to be treated, the age and relative health ofthe patient, the potency of the compound being utilized, the route andform of administration, and other factors.

In general, compounds of this disclosure will be administered aspharmaceutical compositions by any one of the following routes: oral,systemic (e.g., transdermal, intranasal or by suppository), orparenteral (e.g., intramuscular, intravenous or subcutaneous)administration. The preferred manner of administration is oral using aconvenient daily dosage regimen, which can be adjusted according to thedegree of affliction. Compositions can take the form of tablets, pills,capsules, semisolids, powders, sustained release formulations,solutions, suspensions, elixirs, aerosols, or any other appropriatecompositions.

The choice of formulation depends on various factors such as the mode ofdrug administration (e.g., for oral administration, formulations in theform of tablets, pills or capsules, including enteric coated or delayedrelease tablets, pills or capsules are preferred) and thebioavailability of the drug substance.

The compositions are comprised of in general, a compound of thisdisclosure in combination with at least one pharmaceutically acceptableexcipient. Acceptable excipients are non-toxic, aid administration, anddo not adversely affect the therapeutic benefit of the compound of thisdisclosure. Such excipient may be any solid, liquid, semi-solid or, inthe case of an aerosol composition, gaseous excipient that is generallyavailable to one of skill in the art.

Solid pharmaceutical excipients include starch, cellulose, talc,glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silicagel, magnesium stearate, sodium stearate, glycerol monostearate, sodiumchloride, dried skim milk and the like. Liquid and semisolid excipientsmay be selected from glycerol, propylene glycol, water, ethanol andvarious oils, including those of petroleum, animal, vegetable orsynthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesameoil, etc. Preferred liquid carriers, particularly for injectablesolutions, include water, saline, aqueous dextrose, and glycols.

The compounds may be formulated for parenteral administration byinjection, e.g., by bolus injection or continuous infusion. Formulationsfor injection may be presented in unit dosage form, e.g., in ampoules orin multi-dose containers, with an added preservative. The compositionsmay take such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents. The formulations may be presentedin unit-dose or multi-dose containers, for example sealed ampoules andvials, and may be stored in powder form or in a freeze-dried(lyophilized) condition requiring only the addition of the sterileliquid carrier, for example, saline or sterile pyrogen-free water,immediately prior to use. Extemporaneous injection solutions andsuspensions may be prepared from sterile powders, granules and tabletsof the kind previously described.

Formulations for parenteral administration include aqueous andnon-aqueous (oily) sterile injection solutions of the active compoundswhich may contain antioxidants, buffers, bacteriostats and solutes whichrender the formulation isotonic with the blood of the intendedrecipient; and aqueous and non-aqueous sterile suspensions which mayinclude suspending agents and thickening agents. Suitable lipophilicsolvents or vehicles include fatty oils such as sesame oil, or syntheticfatty acid esters, such as ethyl oleate or triglycerides, or liposomes.Aqueous injection suspensions may contain substances which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspension may also containsuitable stabilizers or agents which increase the solubility of thecompounds to allow for the preparation of highly concentrated solutions.

In addition to the formulations described previously, the compounds mayalso be formulated as a depot preparation. Such long acting formulationsmay be administered by implantation (for example subcutaneously orintramuscularly) or by intramuscular injection. Thus, for example, thecompounds may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

For buccal or sublingual administration, the compositions may take theform of tablets, lozenges, pastilles, or gels formulated in conventionalmanner. Such compositions may comprise the active ingredient in aflavored basis such as sucrose and acacia or tragacanth.

The compounds may also be formulated in rectal compositions such assuppositories or retention enemas, e.g., containing conventionalsuppository bases such as cocoa butter, polyethylene glycol, or otherglycerides.

Certain compounds disclosed herein may be administered topically, thatis by non-systemic administration. This includes the application of acompound disclosed herein externally to the epidermis or the buccalcavity and the instillation of such a compound into the ear, eye andnose, such that the compound does not significantly enter the bloodstream. In contrast, systemic administration refers to oral,intravenous, intraperitoneal and intramuscular administration.

Formulations suitable for topical administration include liquid orsemi-liquid preparations suitable for penetration through the skin tothe site of inflammation such as gels, liniments, lotions, creams,ointments or pastes, and drops suitable for administration to the eye,ear or nose. The active ingredient for topical administration maycomprise, for example, from 0.001% to 10% w/w (by weight) of theformulation. In certain embodiments, the active ingredient may compriseas much as 10% w/w. In other embodiments, it may comprise less than 5%w/w. In certain embodiments, the active ingredient may comprise from 2%w/w to 5% w/w. In other embodiments, it may comprise from 0.1% to 1% w/wof the formulation.

For administration by inhalation, compounds may be convenientlydelivered from an insufflator, nebulizer pressurized packs or otherconvenient means of delivering an aerosol spray. Pressurized packs maycomprise a suitable propellant such as dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas. In the case of a pressurized aerosol, the dosageunit may be determined by providing a valve to deliver a metered amount.Alternatively, for administration by inhalation or insufflation, thecompounds according to the disclosure may take the form of a dry powdercomposition, for example a powder mix of the compound and a suitablepowder base such as lactose or starch. The powder composition may bepresented in unit dosage form, in for example, capsules, cartridges,gelatin or blister packs from which the powder may be administered withthe aid of an inhalator or insufflator. Other suitable pharmaceuticalexcipients and their formulations are described in Remington'sPharmaceutical Sciences, edited by E. W. Martin (Mack PublishingCompany, 20th ed., 2000).

The level of the compound in a formulation can vary within the fullrange employed by those skilled in the art. Typically, the formulationwill contain, on a weight percent (wt. %) basis, from about 0.01-99.99wt. % of a compound of this disclosure based on the total formulation,with the balance being one or more suitable pharmaceutical excipients.For example, the compound is present at a level of about 1-80 wt. %.

Combinations and Combination Therapies

The compounds of this disclosure may be used in combination with one ormore other drugs in the treatment of diseases or conditions for whichcompounds of this disclosure or the other drugs may have utility. Suchother drug(s) may be administered, by a route and in an amount commonlyused therefore, contemporaneously or sequentially with a compound ofFormula (I). When a compound of this disclosure is usedcontemporaneously with one or more other drugs, a pharmaceuticalcomposition in unit dosage form containing such other drugs and thecompound of Formula (I) is preferred. However, the combination therapymay also include therapies in which the compound of this disclosure andone or more other drugs are administered on different overlappingschedules. It is also contemplated that when used in combination withone or more other active ingredients, the compounds of Formula (I) andthe other active ingredients may be used in lower doses than when eachis used singly.

Accordingly, the pharmaceutical compositions of Formula (I) also includethose that contain one or more other drugs, in addition to a compound ofFormula (I).

The above combinations include combinations of a compound of thisdisclosure not only with one other drug, but also with two or more otheractive drugs. Likewise, a compound of this disclosure may be used incombination with other drugs that are used in the prevention, treatment,control, amelioration, or reduction of risk of the diseases orconditions for which a compound of this disclosure is useful. Such otherdrugs may be administered, by a route and in an amount commonly usedtherefore, contemporaneously or sequentially with a compound of Formula(I). When a compound of this disclosure is used contemporaneously withone or more other drugs, a pharmaceutical composition containing suchother drugs in addition to the compound of this disclosure can be used.Accordingly, the pharmaceutical compositions of Formula (I) also includethose that also contain one or more other active ingredients, inaddition to a compound of this disclosure. The weight ratio of thecompound of this disclosure to the second active ingredient may bevaried and will depend upon the effective dose of each ingredient.Generally, an effective dose of each will be used.

Where the subject in need is suffering from or at risk of suffering fromcancer, the subject can be treated with a compound of this disclosure inany combination with one or more other anti-cancer agents including butnot limited to:

MAP kinase pathway (RAS/RAF/MEK/ERK) inhibitors including but notlimited to: Vemurafanib (PLX4032), Dabrafenib, Encorafenib (LGX818),TQ-B3233, XL-518 (Cas No. 1029872-29-4, available from ACC Corp);trametinib, selumetinib (AZD6244), TQ-B3234, PD184352, PD325901,TAK-733, pimasertinib, binimetinib, refametinib, cobimetinib (GDC-0973),AZD8330, BVD-523, LTT462, Ulixertinib, AMG510, ARS853, and any RASinhibitors disclosed in patents WO2016049565, WO2016164675,WO2016168540, WO2017015562, WO2017058728, WO2017058768, WO2017058792,WO2017058805, WO2017058807, WO2017058902, WO2017058915, WO2017070256,WO2017087528, WO2017100546, WO2017172979, WO2017201161, WO2018064510,WO2018068017, WO2018119183.

CSF1R inhibitors (PLX3397, LY3022855, etc.) and CSF1R antibodies(IMC-054, RG7155) TGF beta receptor kinase inhibitor such as LY2157299.

BTK inhibitor such as ibrutinib; BCR-ABL inhibitors: Imatinib(Gleevec®); Inilotinib hydrochloride; Nilotinib (Tasigna); Dasatinib(BMS-345825); Bosutinib (SKI-606); Ponatinib (AP24534); Bafetinib(INNO406) Danusertib (PHA-739358), AT9283 (CAS 1133385-83-7);Saracatinib (AZD0530); andA/-[2-[(15,4R)-6-[[4-(Cyclobutylamino)-5-(trifluoromethyl)-2-pyrimidinyl]amino]-1,2,3,4-tetrahydronaphthalen-1,4-imin-9-yl]-2-oxoethyl]-acetamide(PF-03814735, CAS 942487-16-3).

ALK inhibitors: PF-2341066 (XALKOPJ®; crizotinib);5-chloro-N4-(2-(isopropylsulfonyl)phenyl)-N2-(2-methoxy-4(4-(4-methylpiperazin-1-yl)piperidin-yl)phenyl)pyrimidine-2,4-diamine;GSK1838705 A; CH5424802; Ceritinib (ZYKADIA) TQ-B3139, TQ-B3101 PI3Kinhibitors:4-[2-(1H-Indazol-4-yl)-6-[[4-(methylsulfonyl)piperazin-1-yl]methyl]thieno[3,2-d]pyrimidin-4-yl]morpholine(also known as GDC 0941 and described in PCT Publication Nos. WO09/036082 and WO 09/055730),2-Methyl-2-[4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydroimidazo[4,5-c]quinolin-yl]phenyl]propionitrile(also known as BEZ 235 or NVP-BEZ 235, and described in PCT PublicationNo. WO 06/122806).

Vascular Endothelial Growth Factor (VEGF) receptor inhibitors:Bevacizumab (sold under the trademark Avastin® by Genentech/Roche),axitinib,(N-methyl-2-[[3-[(E)-2-pyridin-2-ylethenyl]-1H-indazol-6-yl]sulfanyl]benzamide,also known as AG013736, and described in PCT Publication No. WO01/002369), Brivanib Alaninate((S)((R)-1-(4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-yl)2-aminopropanoate,also known as BMS-582664), motesanib(N-(2,3-dihydro-3,3-dimethyl-1H-indol-6-yl)-2-[(4-pyridinylmethyl)amino]-3-pyridinecarboxamide,and described in PCT Publication No. WO 02/066470), pasireotide (alsoknown as SOM230, and described in PCT Publication No. WO 02/010192),sorafenib (sold under the tradename Nexavar®); AL-2846 MET inhibitorsuch as foretinib, cabozantinib, or crizotinib.

FLT3 inhibitors—sunitinib malate (sold under the tradename Sutent® byPfizer); PKC412 (midostaurin); tanutinib, sorafenib, lestaurtinib,KW-2449, quizartinib (AC220) and crenolanib.

Epidermal growth factor receptor (EGFR) inhibitors: Gefitnib (sold underthe tradename Iressa®),N-[4-[(3-Chloro-4-fluorophenyl)amino]-7-[[(3″S″)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4(dimethylamino)-2-butenamide,sold under the tradename Tovok® by Boehringer Ingelheim), cetuximab(sold under the tradename Erbitux® by Bristol-Myers Squibb), panitumumab(sold under the tradename Vectibix® by Amgen).

HER2 receptor inhibitors: Trastuzumab (sold under the trademarkHerceptin® by Genentech/Roche), neratinib (also known as HKI-272,(2E)-N-[4-[[3-chloro-4-[(pyridin-2-yl)methoxy]phenyl]amino]-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide,and described PCT Publication No. WO 05/028443), lapatinib or lapatinibditosylate (sold under the trademark Tykerb® by GlaxoSmithKline);Trastuzumab emtansine (in the United States, ado-trastuzumab emtansine,trade name Kadcyla)—an antibody-drug conjugate consisting of themonoclonal antibody trastuzumab (Herceptin) linked to the cytotoxicagent mertansine (DM1);

HER dimerization inhibitors: Pertuzumab (sold under the trademarkOmnitarg®, by Genentech).

CD20 antibodies: Rituximab (sold under the trademarks Riuxan® andMabThera® by Genentech/Roche), tositumomab (sold under the trademarksBexxar® by GlaxoSmithKline), ofatumumab (sold under the trademarkArzerra® by GlaxoSmithKline).

Tyrosine kinase inhibitors Erlotinib hydrochloride (sold under thetrademark Tarceva® by Genentech/Roche), Linifanib(N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N′-(2-fluoro-5-methylphenyl)urea,also known as ABT 869, available from Genentech), sunitinib malate (soldunder the tradename Sutent® by Pfizer), bosutinib(4-[(2,4-choro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinoline-3-carbonitrile,also known as SKI-606, and described in U.S. Pat. No. 6,780,996),dasatinib (sold under the tradename Sprycel® by Bristol-Myers Squibb),armala (also known as pazopanib, sold under the tradename Votrient® byGlaxoSmithKline), imatinib and imatinib mesylate (sold under thetradenames Gilvec® and Gleevec® by Novartis).

DNA Synthesis inhibitors: Capecitabine (sold under the trademark Xeloda®by Roche), gemcitabine hydrochloride (sold under the trademark Gemzar byEli Lilly and Company), nelarabine((2R3S,4R,5R)-2-(2-amino-6-methoxy-purin-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol,sold under the tradenames Arranon® and Atriance® by GlaxoSmithKline)

Antineoplastic agents: oxaliplatin (sold under the tradename Eloxatin®ay Sanofi-Aventis and described in U.S. Pat. No. 4,169,846).

Human Granulocyte colony-stimulating factor (G-CSF) modulators:Filgrastim (sold under the tradename Neupogen® by Amgen).

Immunomodulators: Afutuzumab (available from Roche®), pegfilgrastim(sold under the tradename Neulasta® by Amgen), lenalidomide (also knownas CC-5013, sold under the tradename Revlimid®), thalidomide (sold underthe tradename Thalomid®)

CD40 inhibitors: Dacetuzumab (also known as SGN-40 or huS2C6, availablefrom Seattle Genetics, Inc); Pro-apoptotic receptor agonists (PARAs):Dulanermin (also known as AMG-951, available from Amgen/Genentech).

Hedgehog antagonists:2-chloro-N-[4-chloro-3-(2-pyridinyl)phenyl]-4-(methylsulfonyl)-benzamide(also known as GDC-0449, and described in PCT Publication No. WO06/028958);

Phospholipase A2 inhibitors: Anagrelide (sold under the tradenameAgrylin®);

BCL-2 inhibitors:4-[4-[[2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohexen-4-yl]methyl]-1-piperazinyl]-N-[[4-[[(1R)-3-(4-morpholinyl)-1-[(phenylthio)methyl]propyl]amino]-3-[(trifluoromethyl)sulfonyl]phenyl]sulfonyl]benzamide(also known as ABT-263 and described in PCT Publication No. WO09/155386);

MC-1 inhibitors: MIK665, S64315, AMG 397, and AZD5991;

Aromatase inhibitors: Exemestane (sold under the trademark Aromasin® byPfizer), letrozole (sold under the tradename Femara® by Novartis),anastrozole (sold under the tradename Arimidex®);

Topoisomerase I inhibitors: Irinotecan (sold under the trademarkCamptosar® by Pfizer), topotecan hydrochloride (sold under the tradenameHycamtin® by GlaxoSmithKline);

Topoisomerase II inhibitors: etoposide (also known as VP-16 andEtoposide phosphate, sold under the tradenames Toposar®, VePesid® andEtopophos®), teniposide (also known as VM-26, sold under the tradenameVumon®);

mTOR inhibitors: Temsirolimus (sold under the tradename Torisel® byPfizer), ridaforolimus (formally known as deferolimus,(1R,2R,4S)-4-[(2R)-2[(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28Z,30S,32S,35R)-4,18-dihydroxy-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-2,3,10,14,20-pentaoxo-11,36-dioxa-4-azatricyclo[30.3.1.04′9]hexatriaconta-16,24,26,28-tetraen-12-yl]propyl]-2-methoxycyclohexyldimethylphosphinate, also known as AP23573 and MK8669, and described inPCT Publication No. WO 03/064383), everolimus (sold under the tradenameAfinitor® by Novartis);

Proteasome inhibitor such as carfilzomib, MLN9708, delanzomib, orbortezomib

BET inhibitors such as INCB054329, OTX015, CPI-0610; LSD1 inhibitorssuch as GSK2979552, INCB059872; HIF-2a inhibitors such as PT2977 andPT2385;

Osteoclastic bone resorption inhibitors:1-Hydroxy-2-imidazol-1-yl-phosphonoethyl) phosphonic acid monohydrate(sold under the tradename Zometa® by Novartis); CD33 Antibody DrugConjugates: Gemtuzumab ozogamicin (sold under the tradename Mylotarg® byPfizer/Wyeth);

CD22 Antibody Drug Conjugates: Inotuzumab ozogamicin (also referred toas CMC-544 and WAY-207294, available from Hangzhou Sage Chemical Co.,Ltd.); CD20 Antibody Drug Conjugates: Ibritumomab tiuxetan (sold underthe tradename Zevalin®);

Somatostain analogs: octreotide (also known as octreotide acetate, soldunder the tradenames Sandostatin® and Sandostatin LAR®);

Synthetic Interleukin-11 (II-1): oprelvekin (sold under the tradenameNeumega® by Pfizer/Wyeth);

Synthetic erythropoietin: Darbepoetin alfa (sold under the tradenameAranesp® by Amgen);

Receptor Activator for Nuclear Factor κ B (RANK) inhibitors: Denosumab(sold under the tradename Prolia® by Amgen);

Thrombopoietin mimetic peptibodies: Romiplostim (sold under thetradename Nplate® by Amgen;

Cell growth stimulators: Palifermin (sold under the tradename Kepivance®by Amgen);

Anti-Insulin-like Growth Factor-1 receptor (IGF-1R) antibodies:Figitumumab (also known a CP-751,871, available from ACC Corp),robatumumab (CAS No. 934235-44-6);

Anti-CS1 antibodies: Elotuzumab (HuLuc63, CAS No. 915296-00-3);

CD52 antibodies: Alemtuzumab (sold under the tradename Campath®);

Histone deacetylase inhibitors (HDI): Voninostat (sold under thetradename Zolinza® by Merck);

Alkylating agents: Temozolomide (sold under the tradenames Temodar® andTemodal® by Schering-Plough/Merck), dactinomycin (also known asactinomycin-D and sold under the tradename Cosmegen®), melphalan (alsoknown as L-PAM, L-sarcolysin, and phenylalanine mustard, sold under thetradename Alkeran®), altretamine (also known as hexamethylmelamine(HMM), sold under the tradename Hexalen®), carmustine (sold under thetradename BiCNU®), bendamustine (sold under the tradename Treanda®),busulfan (sold under the tradenames Busulfex® and Myleran®), carboplatin(sold under the tradename Paraplatin®), lomustine (also known as CCNU,sold under the tradename CeeNU®), cisplatin (also known as CDDP, soldunder the tradenames Platinol® and Platinol®-AQ), chlorambucil (soldunder the tradename Leukeran®), cyclophosphamide (sold under thetradenames Cytoxan® and Neosar®), dacarbazine (also known as DTIC, DICand imidazole carboxamide, sold under the tradename DTIC-Dome®),altretamine (also known as hexamethylmelamine (HMM) sold under thetradename Hexalen®), ifosfamide (sold under the tradename Ifex®),procarbazine (sold under the tradename Matulane®), mechlorethamine (alsoknown as nitrogen mustard, mustine and mechloroethamine hydrochloride,sold under the tradename Mustargen®), streptozocin (sold under thetradename Zanosar®), thiotepa (also known as thiophosphoamide, TESPA andTSPA, sold under the tradename Thioplex®; Biologic response modifiers:bacillus calmette-guerin (sold under the tradenames theraCys® and TICE®BCG), denileukin diftitox (sold under the tradename Ontak®);

Anti-tumor antibiotics: doxorubicin (sold under the tradenamesAdriamycin® and Rubex®), bleomycin (sold under the tradename lenoxane®),daunorubicin (also known as dauorubicin hydrochloride, daunomycin, andrubidomycin hydrochloride, sold under the tradename Cerubidine®),daunorubicin liposomal (daunorubicin citrate liposome, sold under thetradename DaunoXome®), mitoxantrone (also known as DHAD, sold under thetradename Novantrone®), epirubicin (sold under the tradename Ellence™),idarubicin (sold under the tradenames Idamycin®, Idamycin PFS®),mitomycin C (sold under the tradename Mutamycin®);

Anti-microtubule agents: Estramustine (sold under the tradename Emcyl®);

Cathepsin K inhibitors: Odanacatib (also know as MK-0822,N-(1-cyanocyclopropyl)-4-fluoro-N2-{(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)biphenyl-4-yl]ethyl}-L-leucinamide,available from Lanzhou Chon Chemicals, ACC Corp., and ChemieTek, anddescribed in PCT Publication no. WO 03/075836); Epothilone B analogs:Ixabepilone (sold under the tradename Lxempra® by Bristol-Myers Squibb);

Heat Shock Protein (HSP) inhibitors: Tanespimycin(17-allylamino-17-demethoxygeldanamycin, also known as KOS-953 and17-AAG, available from SIGMA, and described in U.S. Pat. No. 4,261,989),NVP-HSP990, AUY922, AT13387, STA-9090, Debio 0932, KW-2478, XL888,CNF2024, TAS-116

TpoR agonists: Eltrombopag (sold under the tradenames Promacta® andRevolade® by GlaxoSmithKline);

Anti-mitotic agents: Docetaxel (sold under the tradename Taxotere® bySanofi-Aventis); Adrenal steroid inhibitors: aminoglutethimide (soldunder the tradename Cytadren®);

Anti-androgens: Nilutamide (sold under the tradenames Nilandron® andAnandron®), bicalutamide (sold under tradename Casodex®), flutamide(sold under the tradename Fulexin™);

Androgens: Fluoxymesterone (sold under the tradename Halotestin®);

Proteasome inhibitors: Bortezomib (sold under the tradename Velcade®);

CDK (CDK1, CDK2, CDK3, CDK5, CDK7, CDK8, or CDK9) inhibitors includingbut not limited to Alvocidib (pan-CDK inhibitor, also known asflovopirdol or HMR-1275,2-(2-chlorophenyl)-5,7-dihydroxy-8-[(3S,4R)-3-hydroxy-1-methyl-4-piperidinyl]-4-chromenone,and described in U.S. Pat. No. 5,621,002);

CDK4/6 inhibitors pabociclib, ribociclib, abemaciclib, and Trilaciclib;CDK9 inhibitors AZD 4573, P276-00, AT71519M, TP-1287;

Gonadotropin-releasing hormone (GnRH) receptor agonists: Leuprolide orleuprolide acetate (sold under the tradenames Viadure® by Bayer AG,Eligard® by Sanofi-Aventis and Lupron® by Abbott Lab);

Taxane anti-neoplastic agents: Cabazitaxel(1-hydroxy-7,10-dimethoxy-9-oxo-5,20-epoxytax-11-ene-2a,4,13a-triyl-4-acetate-2-benzoate-13-[(2R,3S)-3-{[(tert-butoxy)carbonyl]amino}-2-hydroxy-3-phenylpropanoate),larotaxel((2a,3,4a,5P,7a,10P,13a)-4,10-bis(acetyloxy)-13-({(2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-3-phenylpropanoyl}oxy)-1-hydroxy-9-oxo-5,20-epoxy-7,19-cyclotax-11-en-2-ylbenzoate);

5HTa receptor agonists: Xaliproden (also known as SR57746,1-[2-(2-naphthyl)ethyl]-4-[3-(trifluoromethyl)phenyl]-1,2,3,6-tetrahydropyridine,and described in U.S. Pat. No. 5,266,573); HPC vaccines: Cervarix® soldby GlaxoSmithKline, Gardasil® sold by Merck; Iron Chelating agents:Deferasinox (sold under the tradename Exjade® by Novartis);

Anti-metabolites: Claribine (2-chlorodeoxyadenosine, sold under thetradename leustatin®), 5-fluorouracil (sold under the tradenameAdrucil®), 6-thioguanine (sold under the tradename Purinethol®),pemetrexed (sold under the tradename Alimta®), cytarabine (also known asarabinosylcytosine (Ara-C), sold under the tradename Cytosar-U®),cytarabine liposomal (also known as Liposomal Ara-C, sold under thetradename DepoCyt™), decitabine (sold under the tradename Dacogen®),hydroxyurea (sold under the tradenames Hydrea®, Droxia™ and Mylocel™),fludarabine (sold under the tradename Fludara®), floxuridine (sold underthe tradename FUDR®), cladribine (also known as 2-chlorodeoxyadenosine(2-CdA) sold under the tradename Leustatin™), methotrexate (also knownas amethopterin, methotrexate sodium (MTX), sold under the tradenamesRheumatrex® and Trexall™), pentostatin (sold under the tradenameNipent®);

Bisphosphonates: Pamidronate (sold under the tradename Aredia®),zoledronic acid (sold under the tradename Zometa®); Demethylatingagents: 5-azacitidine (sold under the tradename Vidaza®), decitabine(sold under the tradename Dacogen®);

Plant Alkaloids: Paclitaxel protein-bound (sold under the tradenameAbraxane), vinblastine (also known as vinblastine sulfate,vincaleukoblastine and VLB, sold under the tradenames Alkaban-AQ® andVelban®), vincristine (also known as vincristine sulfate, LCR, and VCR,sold under the tradenames Oncovin® and Vincasar Pfs®), vinorelbine (soldunder the tradename Navelbine®), paclitaxel (sold under the tradenamesTaxol and Onxal™);

Retinoids: Ali tretinoin (sold under the tradename Panretin), tretinoin(all-trans retinoic acid, also known as ATRA, sold under the tradenameVesanoid®), Isotretinoin (13-cis-retinoic acid, sold under thetradenames Accutane®, Amnesteem®, Claravis®, Clarus®, Decutan®,Isotane®, Izotech®, Oratane®, Isotret®, and Sotret®), bexarotene (soldunder the tradename Targretin®);

Glucocorticosteroids: Hydrocortisone (also known as cortisone,hydrocortisone sodium succinate, hydrocortisone sodium phosphate, andsold under the tradenames Ala-Cort®, Hydrocortisone Phosphate,Solu-Cortef®, Hydrocort Acetate® and Lanacort®), dexamethazone((8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-1,17-dihydroxy-17-(2-hydroxyacetyl)-10,13,16-trimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one),prednisolone (sold under the tradenames Delta-Cortel®, Orapred®,Pediapred® and Prelone®), prednisone (sold under the tradenamesDeltasone®, Liquid Red®, Meticorten® and Orasone®), methylprednisolone(also known as 6-Methylprednisolone, Methylprednisolone Acetate,Methylprednisolone Sodium Succinate, sold under the tradenamesDuralone®, Medralone®, Medrol®, M-Prednisol® and Solu-Medrol®);

Cytokines: interleukin-2 (also known as aldesleukin and IL-2, sold underthe tradename Proleukin®), interleukin-11 (also known as oprevelkin,sold under the tradename Neumega®), alpha interferon alfa (also known asIFN-alpha, sold under the tradenames Intron® A, and Roferon-A®); [00209]Estrogen receptor downregulators: Fulvestrant (sold under the tradenameFaslodex®)

Anti-estrogens: tamoxifen (sold under the tradename Novaldex®);Toremifene (sold under the tradename Fareston®);

Selective estrogen receptor modulators (SERMs): Raloxifene (sold underthe tradename Evista®);

Leutinizing hormone releasing hormone (LHRH) agonists: Goserelin (soldunder the tradename Zoladex®); Progesterones: megestrol (also known asmegestrol acetate, sold under the tradename Megace®);

Miscellaneous cytotoxic agents: Arsenic trioxide (sold under thetradename Trisenox®), asparaginase (also known as L-asparaginase,Erwinia L-asparaginase, sold under the tradenames Elspar® andKidrolase®);

One or more additional immune checkpoint inhibitors can be used incombination with a compound as described herein for treatment ofSHP2—associated diseases, disorders or conditions. Exemplary immunecheckpoint inhibitors include inhibitors (smack molecules or biologics)against immune checkpoint molecules such as CD27, CD28, CD40, CD122,CD96, CD73, CD39, CD47, OX40, GITR, CSF1R, JAK, PI3K delta, P3K gamma,TAM kinase, arginase, CD137 (also known as 4-1BB), ICOS, A2AR, A2BR,HIF-2a, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, CD96, TIGIT,PD-1, PD-L1 and PD-L2. In some embodiments, the immune checkpointmolecule is a stimulatory checkpoint molecule selected from CD27, CD28,CD40, ICOS, OX40, GITR, CD137 and STING. In some embodiments, the immunecheckpoint molecule is an inhibitory checkpoint molecule selected fromB7-H3, B7-H4, BTLA, CTLA-4, IDO, TDO, Arginase, KIR, LAG3, PD-1, TIM3,CD96, TIGIT and VISTA. In some embodiments, the compounds providedherein can be used in combination with one or more agents selected fromKIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD160 inhibitors,2B4 inhibitors and TGFR beta inhibitors.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody. In someembodiments, the anti-PD-1 monoclonal antibody is nivolumab,pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, PDR001, orAMP-224. In some embodiments, the anti-PD-1 monoclonal antibody isnivolumab, or pembrolizumab or PDR00L. In some embodiments, the anti-PD1antibody is pembrolizumab.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal antibody. In someembodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736,MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments,the anti-PD-L1 monoclonal antibody is MPDL3280A (atezolizumab) orMED14736 (durvalumab).

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In someembodiments, the anti-CTLA-4 antibody is ipilimumab or tremelimumab. Insome embodiments, the inhibitor of an immune checkpoint molecule is aninhibitor of LAG3, e.g., an anti-LAG3 antibody. In some embodiments, theanti-LAG3 antibody is BMS-986016 or LAG525. In some embodiments, theinhibitor of an immune checkpoint molecule is an inhibitor of GITR,e.g., an anti-GITR antibody. In some embodiments, the anti-GITR antibodyis TRX518 or, MK-4166, INCAGN01876 or MK-1248. In some embodiments, theinhibitor of an immune checkpoint molecule is an inhibitor of OX40,e.g., an anti-OX40 antibody or OX40L fusion protein. In someembodiments, the anti-OX40 antibody is MED10562 or, INCAGN01949,GSK2831781, GSK-3174998, MOXR-0916, PF-04518600 or LAG525. In someembodiments, the OX40L fusion protein is MEDI6383

Compounds of the invention can also be used to increase or enhance animmune response, including increasing the immune response to an antigen;to improve immunization, including increasing vaccine efficacy; and toincrease inflammation. In some embodiments, the compounds of theinvention can be sued to enhance the immune response to vaccinesincluding, but not limited, Listeria vaccines, oncolytic viral vaccines,and cancer vaccines such as GVAX® (granulocyte-macrophagecolony-stimulating factor (GM-CF) gene-transfected tumor cell vaccine).Anti-cancer vaccines include dendritic cells, synthetic peptides, DNAvaccines and recombinant viruses. Other immune-modulatory agents alsoinclude those that block immune cell migration such as antagonists tochemokine receptors, including CCR2 and CCR4; Sting agonists and Tollreceptor agonists.

Other anti-cancer agents also include those that augment the immunesystem such as adjuvants or adoptive T cell transfer. Compounds of thisapplication may be effective in combination with CAR (Chimeric antigenreceptor) T cell treatment as a booster for T cell activation

A compound of the invention can also be used in combination with thefollowing adjunct therapies:

Anti-nausea drugs: NK-1 receptor antagonists: Casopitant (sold under thetradenames Rezonic® and Zunrisa® by GlaxoSmithKline); and

Cytoprotective agents: Amifostine (sold under the tradename Ethyol®),leucovorin (also known as calcium leucovorin, citrovorum factor andfolinic acid).

EXAMPLES

The following preparations of intermediates (References) compounds ofFormula (I) are given to enable those skilled in the art to more clearlyunderstand and to practice the present disclosure.

They should not be considered as limiting the scope of the disclosure,but merely as being illustrative and representative thereof.

Reference 1 Synthesis of(5S)-5,6-dihydrospiro[piperidine-4,4-pyrrolo[1,2-b]pyrazol]-5-aminedihydrochloride

Step 1:1-[1-[(tert-butoxy)(hydroxy)methyl]-4-[hydroxy(methoxy)methyl]piperidin-4-yl]ethan-1-ol

To a solution of[1-[(tert-butoxy)(hydroxy)methyl]piperidin-4-yl](methoxy)methanol (20 g,80.86 mmol, 1.0 equiv) in THF (200 mL) at −78° C. was added LDA (48.52mL, 97.03 mmol, 1.2 equiv) dropwise under nitrogen atmosphere. Afterstirring for 1.5 h at −78° C.˜−60° C., to the above mixture was addedacetaldehyde (5.34 g, 121.29 mmol, 1.5 equiv) dropwise over 5 minutes at−78° C. and the resulting mixture was stirred for additional 2 h at −78°C.˜−40° C. The reaction mixture was then poured into sat. NH₄Cl aq.solution and extracted with EtOAc. The organic layer was washed withbrine, dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by silica gel column chromatography (EtOAc/PE, 0-50%) to afford12 g (50.9% yield) of the title compound as light yellow oil.

Step 2: 1-tert-butyl4-methyl-4-[1-(trifluoromethanesulfonyloxy)ethyl]piperidine-1,4-dicarboxylate

To a solution of 1-tert-butyl 4-methyl4-(1-hydroxyethyl)piperidine-1,4-dicarboxylate (9.5 g, 33.06 mmol, 1equiv) in DCM (100 mL) were added pyridine (10.4 g, 131.48 mmol, 4.0equiv) and (trifluoromethane)sulfonyl trifluoromethanesulfonate (18.7 g,66.27 mmol, 2.0 equiv) dropwise at 0° C. under nitrogen atmosphere.After stirring for 2 h at 0° C., the reaction mixture was quenched withwater at 0° C. The resulting mixture was extracted with CH₂Cl₂. Theorganic layer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to give 20 g (crude) of the titlecompound. This crude product was used directly in next step withoutfurther purification.

Step 3: 1-tert-butyl 4-methyl 4-ethenylpiperidine-1,4-dicarboxylate

To a stirred solution of 1-tert-butyl 4-methyl4-[1-(trifluoromethanesulfonyloxy)-ethyl]piperidine-1,4-dicarboxylate(20 g, crude) in DCM (300 mL) was added DBU (28.50 mL, 187.18 mmol) atrt under nitrogen atmosphere. After stirring for 4 h at rt, the reactionmixture was concentrated under reduced pressure and the residue waspurified by silica gel column chromatography (EtOAc/PE, 6%) to affordthe title compound (4.5 g, 55.2% yield for two steps) as light yellowoil.

Step 4: 1-[(tert-butoxy)carbonyl]-4-ethenylpiperidine-4-carboxylic acid

To a solution of 1-tert-butyl 4-methyl4-ethenylpiperidine-1,4-dicarboxylate (4.8 g, 17.82 mmol, 1.0 equiv) inMeOH (40 mL) were added water (10 mL) and LiOH (2.35 g, 98.01 mmol, 5.5equiv) at room temperature. After stirring for 16 h at rt, the mixturewas acidified to pH=5 with 0.5 M HCl aq. solution. The reaction mixturewas then extracted with CH₂Cl₂. The combined organic layers were washedwith brine, dried over anhydrous Na₂SO₄ and concentrated to give thetitle compound (4.5 g, 98.9% yield) as a light yellow oil which was usedfor next step without further purification.

Step 5: tert-butyl4-ethenyl-4-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate

To a solution of 1-[(tert-butoxy)carbonyl]-4-ethenylpiperidine4-carboxylic acid (4.5 g, 17.62 mmol, 1.0 equiv) andmethoxy(methyl)amine (1.61 g, 26.43 mmd, 1.5 equiv) in DCM (70 mL) wereadded HATU (13.40 g, 35.25 mmol, 2.0 equiv) and Et₃N (5.35 g, 52.86mmol, 3.0 equiv) at rt under nitrogen atmosphere. After stirring for 12h at rt, the reaction mixture was quenched with water at roomtemperature and extracted with DCM. The organic layer was washed withbrine, dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by silica gel column chromatography (EtOAc/PE, 5%) to affordthe title compound (5 g, 95% yield) as a white solid.

Step 6: tert-butyl 4-acetyl-4-ethenylpiperidine-1-carboxylate

To a solution of tert-butyl4-ethenyl-4-[(methyl)carbamoyl]piperidine-carboxylate (5 g, 16.75 mmol,1.0 equiv) in THF (60 mL) was added 2.5 M CH₃MgBr (16.76 mL, 41.89 mmol,2.50 equiv) dropwise at 0° C. under nitrogen atmosphere. After stirringfor 12 h at rt, the reaction was quenched with sat. NH₄Cl aq. solutionat 0° C. and the mixture was extracted with EtOAc. The organic layer waswashed with brine, dried over anhydrous Na₂SO₄ and concentrated. Theresidue was purified by silica gel column chromatography (EtOAc/PE, 1/3)to afford the title compound (3.5 g, 82.4% yield) as light yellow oil.

Step 7: tert-butyl4-[(2Z)-3-(dimethylamino)prop-2-enoyl]-4-ethenylpiperidine-1-carboxylate

A solution of tert-butyl 4-acetyl-4-ethenylpiperidine-1-carboxylate (2.2g, 8.68 mmd, 1.0 equiv) in[(tert-butoxy)(dimethylamino)methyl]dimethylamine (2 mL, 9.69 mmol, 1.1equiv.) was stirred for 4 h at 100° C. under nitrogen atmosphere. Thereaction mixture was concentrated under reduced pressure. The residuewas purified by silica gel column chromatography, eluted with PE/EtOAc(1:1) to afford the title compound (1.6 g, 59.7% yield) as light yellowoil.

Step 8: tert-butyl 4-thenyl-4-(H-pyrazol-5-yl)piperidine-1-carboxylate

To a stirred solution of tert-butyl4-[(2Z)-3-(dimethylamino)prop-2-enoyl]-4-ethenylpiperidine-1-carboxylate(2.2 g, 7.13 mmol, 1.0 equiv.) in EtOH (50 mL) was added hydrazinemonohydrate (0.54 g, 10.78 mmol, 1.5 equiv) at 25° C. under nitrogenatmosphere. After stirring for 16 h at 25° C., the reaction was quenchedwith water and the resulting mixture was extracted with DCM. The organiclayer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated. The residue was purified by silica gel columnchromatography, eluted with EtOAc/PE (30%-60%) to afford the titlecompound (1.6 g, 80.8% yield) as a white solid.

Step 9: tert-butyl4-(oxiran-2-yl)-4-(1H-pyrazol-5-yl)piperidine-1-carboxylate

To a stirred mixture of tert-butyl4-ethenyl-4-(1H-pyrazol-5-yl)piperidine-1-carboxylate (2 g, 7.2 mmol,1.0 equiv) and methyltrioxorhenium (VII)(179.72 mg, 0.72 mmol, 0.1equiv) in DCM (30 mL) were added pyridine (228.14 mg, 2.88 mmol, 0.4equiv) and H₂O₂ (30%))(1.23 g, 10.85 mmol, 1.5 equiv) at rt. Afterstirring for 16 h at rt, the reaction was quenched with water andextracted with DCM. The organic layer was washed with brine, dried overanhydrous Na₂SO₄ and concentrated. The residue was purified by silicagel column chromatography, eluted with EtOAc/PE (30%-60%) to afford thetittle compound (0.8 g, 37.82%) as a white solid.

Step 10: tert-butyl5-hydroxy-5,6-dihydrospiro[piperidine-4,4-pyrrolo[1,2-b]pyrazole]-1-carboxylate

To a stirred solution of tert-butyl4-(oxiran-2-yl)-4-(1H-pyrazol-5-yl)piperidine-1-carboxylate (0.7 g, 2.38mmol, 1.0 equiv) in THF (10 mL) were added LiBr (0.62 g, 7.15 mmol, 3.0equiv) and CH₃COOH (0.43 g, 7.15 mmol, 3.0 equiv) at room temperature.After stirring for 16 h at rt, the reaction mixture was stirred at 45°C. for 8 h. After cooling to rt, the reaction mixture was quenched withsat. NaHCO₃ aq. solution and the mixture was extracted with EtOAc. Theorganic layer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated. The residue was purified by silica gel columnchromatography, eluted with EtOAc/PE (30%-100%) to afford the titlecompound (0.4 g, 57.1% yield) as a white solid.

Step 11: tert-butyl5-oxo-5,6-dihydrospiro[piperidine-4,4-pyrrolo[1,2-b]pyrazole]-1-carboxylate

To a solution of tert-butyl5-hydroxy-5,6-dihydrospiro[piperidine-4,4-pyrrolo[1,2-b]pyrazole]-1-carboxylate(0.4 g, 1.36 mmol, 1.0 equiv) in DCM (8 mL) was added Dess-Martin (0.87g, 2.04 mmol, 1.5 equiv) at rt. After stirring for 4 h at roomtemperature, the reaction mixture was quenched with sat. NaHCO₃ aq.solution at room temperature and extracted with DCM. The organic layerwas washed with brine, dried over anhydrous Na₂SO₄ and concentrated. Theresidue was purified by silica gel column chromatography (EtOAc/PE,20%-60%) to afford the title compound (0.36 g, 90.62%) as a white solid.

Step 12: tert-butyl(S)-5-[(R)-2-methylpropane-2-sulfinyl)amino]-5,6-dihydrospiro[piperidine-4,4-pyrrolo[1,2-b]pyrazole]-1-carboxylate

To a solution of tert-butyl5-oxo-5,6-dihydrospiro[piperidine-4,4-pyrrolo[1,2-b]pyrazole]-1-carboxylate(0.36 g, 1.23 mmol, 1.0 equiv.) in THF (6 mL) was added(R)-2-methylpropane-2-sulfinamide (0.30 g, 2.47 mmol, 2.0 equiv.) andTi(OEt)₄ (1.13 g, 4.94 mmol, 4.0 equiv.) at rt under nitrogenatmosphere. After stirring for 4 hrs at 75° C., the reaction mixture wascooled to −20° C. To the above mixture was added MeOH (1 mL) and LiBH₄(40.38 mg, 1.85 mmol, 1.50 equiv) at −20° C. After stirring foradditional 6 h at 0° C., the reaction mixture was quenched with sat.NH₄Cl aq. solution at 0° C. The mixture was then filtered and the filtercake was washed with EtOAc. The filtrate was concentrated under reducedpressure and the residue was dissolved in MeOH (3 mL). To the abovemixture was added LiBH₄(80.75 mg, 3.71 mmol, 3.0 equiv) at roomtemperature. The resulting mixture was stirred for additional 8 h at 45°C. The reaction mixture was quenched with sat. NH₄Cl aq. solution at 0°C. The resulting mixture was extracted with EtOAc. The organic layer waswashed with brine, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography, eluted with EtOAc/PE (30%-70%) to afford the titlecompound (200 mg, 40.8% yield) as a white solid.

Step 13:(5S)-5,6-dihydrospiro[piperidine-4,4-pyrrolo[1,2-b]pyrazol]-5-aminedihydrochloride

To a stirred solution of tert-butyl(S)-5-[(R)-2-methylpropane-2-sulfinyl)amino]-5,6-dihydrospiro[piperidine-4,4-pyrrolo[1,2-b]pyrazole]-1-carboxylate(100 mg, 0.252 mmol, 1.0 equiv) in 1,4-dioxane (0.5 mL) was added thesolution of HCl in dioxane (4 M, 0.50 mL) dropwise at room temperature.After stirring for 30 mins at rt, the reaction mixture was concentratedunder reduced pressure. To the residue was added Et₂O (1 mL) and theprecipitate was collected by filtration to afford the title compound (60mg, 89.7% yield) as a white solid.

Example 1 Synthesis of(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((S)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)methanol

Step 1: tert-butyl(2S)-2-[[(2-fluoropyridin-3-yl)oxy]methyl]pyrrolidine-1-carboxylate

To a stirred mixture of 2-fluoropyridin-3-ol (1 g, 8.84 mmol, 1.00equiv.) and tert-butyl (2S)-2-(hydroxylmethyl)pyrrolidine-1-carboxylate(2.14 g, 10.61 mmol, 1.2 equiv.) in THF (15 mL) were added PPh₃ (3.48 g,13.26 mmol, 1.50 equiv) and DEAD (2.31 g, 13.26 mmol, 1.5 equiv.) atroom temperature under nitrogen atmosphere. After stirring for 16 h atroom temperature, the reaction mixture was concentrated under reducedpressure. The residue was purified by silica gel column chromatography,eluted with PE/EtOAc (15:1) to afford the title compound (2.5 g, 95.4%yield) as a light yellow oil.

Step 2: 2-fluoro-3-[[(2S)-pyrrolidin-2-yl]methoxy]pyridinedihydrochloride

To a stirred solution of tert-butyl(2S)-2-[[(2-fluoropyridin-3-yl)oxy]methyl]-pyrrolidine-1-carboxylate(2500 mg, 8.43 mmol, 1.00 equiv) in DCM (15 mL) was added hydrogenchloride (4 M in dioxane) (15 mL) at room temperature. After stirring atrt for 4 h, the reaction mixture was concentrated under vacuum to affordthe title compound (2.20 g, 96.8% yield) as a white solid.

Step 3:(S)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine

To a stirred solution of2-fluoro-3-[[(2S)-pyrrolidin-2-yl]methoxy]pyridine dihydrochloride (2.20g, 8.17 mmol, 1.00 equiv) in ethanol (50 mL) was added K₂CO₃ (5.64 g,40.87 mmol, 5.00 equiv) at room temperature and the resulting mixturewas stirred for 12 h at 65° C. The mixture was then filtered and thefiltrate was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography, eluted with PE/EtOAc (3:1)to afford the title compound (1.34 g, 93% yield) as colorless oil.

Step 4:(S)-4-iodo-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine

To a stirred solution of(S)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine (600mg, 3.41 mmol, 1.00 equiv) in THF (15 mL) was added dropwisen-butyllithium solution (2.5 M in hexane, 3.4 mL, 8.5 mmol, 2.50 equiv)at −78° C. under N2 atmosphere. The reaction mixture was allowed to warmto 0° C. and stirred for 1.5 h. To the above mixture was added to asolution of I₂ (950.60 mg, 3.74 mmol, 1.10 equiv) in THF (2 mL) dropwiseat −78° C. The resulting mixture was allowed to warm to room temperatureand stirred for 2 h at room temperature. The reaction mixture wasquenched with sat. NH₄Cl aq. solution and diluted with EtOAc. Theorganic layer was washed with brine, dried over anhydrous Na₂SO₄. Afterfiltration, the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography, eluted withPE/EtOAc (3:1) to afford the title compound (700 mg, 68% yield) as ayellow solid.

Step 5: 2-ethylhexyl3-(((S)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-][1,4]oxazin-4-yl)thio)propanoate

To a stirred mixture of(S)-4-iodo-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine(150.00 mg, 0.496 mmol, 1.00 equiv), 2-ethylhexyl 3-sulfanylpropanoate(162.62 mg, 0.745 mmol, 1.50 equiv), Pd₂(dba)₃ (22.73 mg, 0.025 mmol,0.05 equiv) and Xantphos (14.36 mg, 0.025 mmol, 0.05 equiv) in1,4-dioxane (2 mL) was added DIEA (192.51 mg, 1.489 mmol, 3.00 equiv) atroom temperature under nitrogen atmosphere. After stirring for 1 h at90° C., the reaction mixture was concentrated under reduced pressure.The residue was purified by silica gel column chromatography, elutedwith EtOAc/PE (0-30%) to afford the title compound (160 mg, 82% yield)as a light yellow solid.

Step 6: potassium(S)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine-4-thiolate

To a stirred solution of 2-ethylhexyl3-(((S)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]-pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)propanoate(140.00 mg, 0.357 mmol, 1.0 equiv) in THF (2 mL) was added 1.0 M t-BuOK(0.43 mL, 0.43 mmol, 1.20 equiv) at −10° C. After stirring for 0.5 h at0° C., the reaction mixture was diluted with petroleum ether. Theprecipitated solids were collected by filtration and washed with ethylacetate to afford the title compound (75 mg, 85% yield) as a lightyellow solid.

Step 7: methyl6-bromo-3-[(3S,4S)-4-[[(ter-butoxy)carbonyl]amino]-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]pyrazine-2-carboxylate

A solution of methyl 3,6-dibromopyrazine-2-carboxylate (500 mg, 1.690mmol, 1 equiv), (3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-aminedihydrochloride (493.05 mg, 2.028 mmol, 1.2 equiv) and DIEA (1091.88 mg,8.448 mmol, 5.0 equiv) in DMA (10 mL) was stirred for 2 h at 55° C.Di-tert-butyl dicarbonate (55233 mg, 2.531 mmol, 1.5 equiv) was thenadded and the resulting mixture was stirred for 2 h at room temperature.The reaction mixture was diluted with water and extracted with EtOAc.The organic layer was washed with water and brine, dried over anhydrousNa₂SO₄ and concentrated. The residue was purified by silica gel columnchromatography, eluted with PE/EtOAc=1:1 to afford the title compound(615 mg, 2 steps yield 75%) as yellow oil.

Step 8: tert-butylN-[(3S,4S)-8-[5-bromo-3-(hydroxymethyl)pyrazin-2-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl]carbamate

To a stirred solution of methyl6-bromo-3-[(3S,4)-4-[[(tert-butoxy)carbonyl]-amino]-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]pyrazine-2-carboxylate(150 mg, 0.309 mmol, 1 equiv) in DCM (3.75 mL) was added DIBAL-H (1.0 Min DCM, 1.24 m1, 1.240 mmol, 4.01 equiv) dropwise at −78° C. undernitrogen atmosphere. The resulting mixture was stirred for 30 min at−78° C. under nitrogen atmosphere, warmed to rt then quenched by addingsat. Rochelle's salt aq. solution. The resulting mixture was extractedwith EtOAc. The organic layer was washed with brine, dried overanhydrous Na₂SO₄ and concentrated. The residue was purified by silicagel column chromatography, eluted with EtOAc/PE (0-50%) to afford thetitle compound (65 mg, 46%) as a yellow solid.

Step 9: tert-butyl((3S,4S)-8-(3-(hydroxymethyl)-5-(((S)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate

To a stirred mixture of tert-butylN-[(3S,4S)-8-[5-bromo-3-(hydroxymethyl)pyrazin-2-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl]carbamate(25.00 mg, 0.055 mmol, 1.00 equiv), potassium(S)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine-4-thiolate(20.20 mg, 0.082 mmol, 1.50 equiv), Pd₂(dba)₃ (15.02 mg, 0.0164 mmol,0.30 equiv) and Xantphos (9.49 mg, 0.0164 mmol, 0.30 equiv) in1,4-dioxane (1 mL) was added DIEA (21.19 mg, 0.164 mmol, 3.00 equiv) atroom temperature under nitrogen atmosphere. After stirring for 1.5 h at100° C., the reaction mixture was concentrated under reduced pressure.The residue was purified by silica gel column chromatography, elutedwith EtOAc/PE (50%-100%) to afford the title compound (25 mg, 78% yield)as a light yellow solid.

Step 10:(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6((S)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)methanolformate

To a stirred solution of tert-butyl((3S,4S)-8(3-(hydroxymethyl)-5-(((S)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate(20.00 mg, 0.034 mmol, 1.0 equiv) in DCM (1.5 mL) was added TFA (0.3 mL)at room temperature. After stirring for 5 h at room temperature, thereaction mixture was concentrated under reduced pressure. The crudeproduct was purified by Prep-HPLC to afford the title compound (7 mg,39% yield) as a light yellow solid. MS (ES, m/z): [M+1]⁺=485.2.

Example 2 Synthesis of(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((R)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)methanol

Compound 2 was synthesized by the method described in Example 1 usingtert-butyl(2R)-2-(hydroxylmethyl)pyrrolidine-1-carboxylate instead oftert-butyl (2S)-2-(hydroxylmethyl)-pyrrolidine-1-carboxylate in Step 1.MS (ES, m/z): [M+1]⁺=485.3.

Example 3 Synthesis of(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((6aS,8S)-8-fluoro-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)methanol

Step 1: tert-butyl(2S,4S)-4-fluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate

To a stirred solution of(2S,4S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid(2.33 g, 9.99 mmol, 1.0 equiv) in THF (25 mL) was added BH₃—Me₂S (2.8mL, 29.5 mmol, 3.0 equiv) dropwise at 0-5° C. under nitrogen atmosphereand the resulting mixture was stirred overnight at room temperature. Themixture was cooled to 0° C. and quenched with MeOH. The resultingmixture was concentrated under reduced pressure and the residue waspurified by silica gel column chromatography, eluted with EtOAc/PE (1/1)to give the title compound (2.0 g, 91.3%).

Step 2:tert-butyl(2S,4S)-4-fluoro-2-[[(2-fluoro-4-iodopyridin-3-yl)oxy]methyl]pyrrolidine-1-carboxylate

To a stirred solution of 2-fluoro-4-iodopyridin-3-ol (436 mg, 1.82 mmol,1.0 equiv), tert-butyl(2S,4S)-4-fluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate (400 mg,1.82 mmol, 1.0 equiv) and PPh₃ (717 mg, 2.73 mmol, 1.5 equiv) in THF(4.00 mL) was added DEAD (476 mg, 2.73 mmol, 1.5 equiv) dropwise at 0°C. under nitrogen atmosphere. The resulting mixture was stirredovernight at room temperature under nitrogen atmosphere. The reactionmixture was quenched with water and the resulting mixture was extractedwith EtOAc. The combined organic layers were washed with water andbrine, dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by silica gel column chromatography, eluted with EtOAc/PE(0-50%), to afford the title compound (610 mg, 75.5%).

Step 3:2-fluoro-3-(((2S,4S)-4-fluoropyrrolidin-2-yl)methoxy)-4-iodopyridinehydrochloride

To a stirred solution of tert-butyl(2S,4S)-4-fluoro-2-[[(2-fluoro-4-iodopyridin-3-yl)oxy]methyl]pyrrolidine-1-carboxylate(560 mg, 1.272 mmol, 1.0 equiv) in 1,4-dioxane (5 mL) was added asolution of 3.3 M HCl in 1,4-dioxane (5 mL, 16.5 mmol, 13 equiv)dropwise at 0° C. After stirring at room temperature for 1 hour, thereaction mixture was concentrated under reduced pressure and the residuewas triturated with Et₂O. The solid was collected by filtration anddried under vacuum to give product as HCl salt (375 mg, 78.3%).

Step 4:(6aS,8S)-8-fluoro-4-iodo-a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine

A mixture of2-fluoro-3-(((2S,4S)-4-fluoropyrrolidin-2-yl)methoxy)-4-iodopyridinehydrochloride (370 mg, 0.983 mmol, 1.0 equiv) and K₂CO₃ (407 mg, 2.95mmol, 3.0 equiv) in EtOH (4 mL) was stirred for 2 h at 60° C. Theresulting mixture was diluted with water and extracted with EtOAc. Thecombined organic layers were washed with water and brine, dried overanhydrous Na₂SO₄ and concentrated. The residue was purified by silicagel column chromatography, eluted with EtOAc/PE (0-30%), to afford thetitle compound (245 mg, 77.9%).

Step 5: 2-ethylhexyl3-([5-[(3S,4S)-4-[(tert-butoxycarbonyl)amino]-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]6-(hydroxymethyl)pyrazin-2-yl]sulfanyl)propanoate

A solution of tert-butylN-[(3S,4S)-8-[5-bromo-3-(hydroxymethyl)pyrazin-2-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl]carbamate(580.0 mg, 1.27 mmol, 1.0 equiv),2-ethylhexyl 3-sulfanylpropanoate(332.29 mg, 1.52 mmol, 1.2 equiv), Pd₂(dba)₃ (116.1 mg, 0.127 mmol, 0.10equiv), XantPhos (73.38 mg, 0.127 mmol, 0.10 equiv) and DIEA (491.69 mg,3.804 mmol, 3.00 equiv) in 1,4-dioxane (12.0 mL) was stirred for 1 h at100° C. under nitrogen atmosphere. The resulting mixture wasconcentrated under vacuum and the residue was purified by silica gelcolumn chromatography, eluted with EtOAc/PE (0-50/), to afford the titlecompound (600 mg, 79.54%).

Step 6: sodium5-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]-decan-8-yl)-6-(hydroxymethyl)pyrazine-2-thiolate

To a stirred solution of 2-ethylhexyl3-([5-[(3S,4S)-4-[(tert-butoxycarbonyl)amino]-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-(hydroxymethyl)pyrazin-2-yl]sulfanyl)propanoate(680.0 mg, 1.14 mmol, 1.0 equiv) in CH₃OH (6.80 mL) was added CH₃₀Na(247.04 mg, 1.372 mmol, 1.20 equiv, 30% in MeOH) dropwise at 5° C. Afterstirring at rt for 16 h, the reaction mixture was concentrated undervacuum and the residue was triturated with Et₂O to afford the titlecompound (390 mg, crude)), which was used for next step without furtherpurification.

Step 7: tert-butyl((3S,4S)-8-(5-(((6aS,8S)-8-fluoro-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrido[1,2-d][1,4]oxazin-4-yl)thio)-3-(hydroxymethyl)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate

A solution of(6aS,8S)-8-fluoro-4-iodo-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine(30.00 mg, 0.094 mmol, 1.0 equiv), sodium5-((3S,4S)-4-((ter-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(hydroxymethyl)pyrazine-2-thiolate(48.64 mg, 0.112 mmol, 1.2 equiv), Pd₂(dba)₃ (25.75 mg, 0.028 mmol, 0.30equiv), XantPhos (16.27 mg, 0.028 mmol, 0.30 equiv) and DIEA (36.34 mg,0.281 mmol, 3.00 equiv) in dioxane (0.90 mL) was stirred for 1 h at 80°C. under nitrogen atmosphere. After cooling to rt, the reaction mixturewas diluted with water, extracted with EtOAc. The organic layer waswashed with water and brine, dried over Na₂SO₄ and concentrated. Theresidue was purified by silica gel column chromatography, eluted withMeOH/CH₂Cl₂ (0-10%), to afford the title compound (32 mg, 56.4%).

Step 8:(3-((S)-4-amino-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((6aS,8S)-8-fluoro-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)methanol

To a solution tert-butyl((3S,4S)-8-(5-(((6aS,8S)-8-fluoro-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)-3-(hydroxymethyl)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate(26 mg, 0.043 mmol, 1.00 equiv) in DCM (1.2 mL) was added TFA (0.4 mL,5.23 mmol, 122 equiv) dropwise at 5° C. After stirring at rt for 1 h,the reaction mixture was concentrated under vacuum and the residue waspurified by Prep-HPLC to give the title compound (3.1 mg, 14.30%). MS(ES, m/z) [M+1]⁺=5032.

Example 4 Synthesis of(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((6aS,8R)-8-fluoro.6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)methanol

The title compound was synthesized by the method described in Example 3using (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylicacid in Step 1. MS (ES, m/z): [M+1]⁺=503.3.

Example 5 Synthesis of(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((6aS,8S)-8-methoxy-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)methanol

Step 1: 1-tert-butyl2-methyl(2S,4S)-4-[(tert-butyldimethylsilyl)oxy]pyrrolidine-1,2-dicarboxylate

To a stirred solution of 1-tert-butyl 2-methyl(2S,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate (6.0 g, 24.46 mmol, 1.0equiv) and imidazole (2.5 g, 36.72 mmol, 1.50 equiv) in DCM (60 mL) wasadded TBS-Cl (5.53 g, 36.69 mmol, 1.50 equiv) in portions at 0-5° C.After stirring overnight at room temperature, the reaction mixture wasquenched with MeOH and water, and the resulting mixture was extractedwith EtOAc. The combined organic layers were washed with water andbrine, dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by silica gel column chromatography, eluted with EtOAc/PE(0-10%), to afford the title compound (9.0 g, 102.3%).

Step 2:tert-butyl(2S,4S)-4[(tert-butyldimethylsilyl)oxy]-2-(hydroxymethyl)pyrrolidine-1-carboxylate

To a stirred mixture of 1-tert-butyl 2-methyl(2S,4S)-4-[(tert-butyldimethylsilyl)oxy]-pyrrolidine-1,2-dicarboxylate(3.0 g, 8.344 mmol, 1.0 equiv) in THF (30 mL) was added LiAlH₄ (475 mg,12.516 mmol, 1.50 equiv) in portions at 0° C. under nitrogen atmosphereand the resulting mixture was stirred for 2 h at room temperature undernitrogen atmosphere. After cooling to 0° C., the reaction mixture wasquenched with sat. aq. Na₂SO₄ solution. The resulting mixture wasfiltered and the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography, eluted withEtOAc/PE (0-100%), to afford the title compound (1.6 g, 57.8%).

Step 3: tert-butyl (2S,4S)-4-[(tert-butyldimethylsilyl)oxy]-2-[[(2-fluoro-4-iodopyridin-3-yl)oxy]methyl]pyrrolidine-1-carboxylate

To a stirred mixture of 2-fluoro-4-iodopyridin-3-ol (400 mg, 1.674 mmol,1.0 equiv), tert-butyl(2S,4S)-4-[(tert-butyldimethylsilyl)oxy]-2-(hydroxymethyl)pyrrolidine-1-carboxylate(555 mg, 1.674 mmol, 1.00 equiv) and PPh₃ (658 mg, 2.511 mmol, 1.50equiv) in THF (4 mL) was added DEAD (437 mg. 2.51 mmol, 1.50 equiv)dropwise at 0° C. under nitrogen atmosphere. The resulting mixture wasstirred for 2 h at room temperature under nitrogen atmosphere, thenquenched with water at 0° C. and extracted with EtOAc. The combinedorganic layers were washed with water and brine, dried over anhydrousNa₂SO₄ and concentrated. The residue was purified by silica gel columnchromatography, eluted with EtOAc/PE (0-30%), to afford the titlecompound (735 mg, 79.4%).

Step 4: (3S,5S)-5-[[(2-fluoro-4-iodopyridin-3-yl)oxy]methyl]pyrrolidin-3-olhydrochloride

To a stirred solution of tert-butyl(2S,4S)-4-[(tert-butyldimethylsilyl)oxy]-2-[[(2-fluoro-4-iodopyridin-3-yl)oxy]methyl]pyrrolidine-1-carboxylate(750 mg, 1.357 mmol, 1.0 equiv) was added a solution of 3.0 M HCl in1,4-dioxane (5 mL, 15 mmol, 11 equiv) dropwise at 0-5° C. After stirringat room temperature for 1 h, the reaction mixture was concentrated underreduced pressure and the residue was triturated with Et₂O. Theprecipitates were collected by filtration and dried under reducedpressure to give the title compound (400 mg, 78.7%).

Step 5:(6aS,8S)-4-iodo-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-8-ol

A mixture of (3S,5S)-5-[[(2-fluoro-4-iodopyridin-3-yl)oxy]methyl]pyrrolidin-3-olhydrochloride (400 mg, 1.068 mmol, 1.00 equiv) and K₂CO₃ (443 mg, 3.205mmol, 3.00 equiv) in EtOH (4 mL) was stirred for 2 h at 60° C. Aftercooling to rt, the resulting mixture was diluted with water andextracted with EtOAc. The combined organic layers were washed with waterand brine, dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by silica gel column chromatography, eluted with EtOAc/PE(0-40), to afford the title compound (300 mg, 88.3%).

Step 6:(6aS,8S)-4-iodo-8-methoxy-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine

To a stirred solution of(6aS,8S)-4-iodo-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-8-ol(100.00 mg, 0.314 mmol, 1.0 equiv) and Ag₂O (364.23 mg, 1.572 mmol, 5.0equiv) in DMF (1.00 mL) was added Me (133.86 mg, 0.943 mmol, 3.00 equiv)dropwise at room temperature and the resulting mixture was stirred for 4h at 50° C. After cooling to room temperature, the reaction mixture wasfiltered. The filtrate was washed with H₂O and brine, dried overanhydrous Na₂SO₄ and concentrated. The residue was purified by silicagel column chromatography, eluted with PE/EA (2/1), to afford the titlecompound (89 mg, 85.2%).

Step 7:tert-butyl((3S,4S)-8-(3-(hydroxymethyl)-5-(((6aS,8S)-8-methoxy-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate

To a stirred mixture of(6aS,8S)-4-iodo-8-methoxy-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine(30.00 mg, 0.090 mmol, 1.0 equiv) and tert-butylN-[(3S,4S)-8-[3-(hydroxymethyl)-5-sulfanylpyrazin-2-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl]carbamate(37.08 mg, 0.090 mmol, 1.0 equiv) in dioxane (0.30 mL) were addedPd₂(dba)₃ (24.81 mg, 0.027 mmol, 030 equiv), Xantphos (15.68 mg, 0.027mmol, 0.30 equiv) and DIEA (35.02 mg, 0.271 mmol, 3.0 equiv) at roomtemperature under N2 atmosphere. The resulting mixture was stirred for 1h at 80° C. under N2 atmosphere. After cooling to room temperature, thereaction mixture was concentrated under vacuum and the residue waspurified by silica gel column chromatography, eluted with DCM/MeOH(10/1), to afford the title compound (25 mg, 45.6%).

Step 8:(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-((6aS,8S)-8-methoxy-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)methanolformate

TFA (1.3 mL) was added to a solution oftert-butyl((3S,4S)-8-(3-(hydroxymethyl)-5-(((6aS,8S)-8-methoxy-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate(130.0 mg, 0.21 mmol, 1.0 equiv) in DCM (3.0 mL) at room temperature.After stirring at rt for 2 h, the reaction solution was concentrated andthe residue was purified by Prep-HPLC to give product (19 mg, 16.1%). MS(ES, m/z): [M+1]⁺=515.3.

Example 6 Synthesis of(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((6aS,8R)-8-methoxy-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)methanol

Step 1:(6aS,8R)-4-iodo-8-methoxy-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine

Compound(6aS,8R)-4-iodo-8-methoxy-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazinewas synthesized by the method described in Example 5, Steps 1-6 using1-(tert-butyl) 2-methyl (2S,4S)-4-hydroxypyrrolidine-1,2-dicarboxylatein Step 1.

Step 2:(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((6aS,8R)-8-methoxy-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)methanol

(3-((3S,4S)-4-Amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-yl)-6-(((6aS,8R)-8-methoxy-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)methanolwas synthesized by proceeding analogously as described in Example 5,Steps 7-8. MS (ES, m/z): [M+1]⁺=515.3.

Example 7 Synthesis of(6aS,8S)-4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-8-ol

The title compound was synthesized by the method as described in Example5, Steps 7-8 using(6aS,8S)-4-iodo-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-8-olin Step 7. MS (ES, m/z): [M+1]⁺=501.3.

Example 8 Synthesis of(6aS,8R)-4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-8-ol

The title compound was synthesized by proceeding analogously asdescribed in Example 7. MS (ES, m/z): [M+1]⁺=501.3.

Example 9 Synthesis of(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((6aR,8R)-8-methoxy-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)methanol

The title compound was synthesized by proceeding analogously asdescribed in Example 5, Steps 2-8 using 1-tert-butyl 2-methyl(2R,4R)-4-methoxy-pyrrolidine-1,2-dicarboxylate in Step 2. MS (ES, m/z):[M+1]⁺=515.3.

Example 10 Synthesis of(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((6aR,8S)-8-methoxy-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)methanol

The title compound was synthesized by proceeding analogously asdescribed in Example 5 Steps 2-8 using tert-butyl(2R,4S)-2-(hydroxymethyl)-4-methoxypyrrolidine-1-carboxylate in Step 2.MS (ES, m/z): [M+1]⁺=515.2

Example 11 Synthesis of(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-((6aS,8S)-8-(((S)-tetrahydrofuran-3-yl)oxy)-6a,7,8,9-tetrahydro-H-pyrid[3,2-b]pyrrolo[,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)methanol

Step 1:(6aS,8S)-4-iodo-8-(((S)-tetrahydrofuran-3-yl)oxy)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine

To a stirred solution of (3R)-oxolan-3-yl 4-methylbenzenesulfonate (457mg, 1.886 mmol, 3 equiv) and(6aS,8S)-4-iodo-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-8-ol(200 mg, 0.629 mmol, 1.00 equiv) in DMF (2.00 mL) was added NaH (88 mg,2.200 mmol, 3.5 equiv, 60%) in portions at 0° C. under nitrogenatmosphere and the resulting mixture was stirred overnight at roomtemperature under nitrogen atmosphere. After cooling to 0° C., thereaction was quenched with water and the resulting mixture was dilutedwith water and extracted with EtOAc. The combined organic layers werewashed with water and brine, dried over anhydrous Na₂SO₄ andconcentrated. The residue was purified by Prep-TLC (EtOAc 100%) toafford the title compound (70 mg, 28.7%).

Step 2:(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((6aS,8S)-8-(((S)-tetrahydrofuran-3-yl)oxy)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)methanol

The title compound was synthesized from(6aS,8S)-4-iodo-8-(((S)-tetrahydrofuran-3-yl)oxy)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazineby proceeding analogously as described in Example 5, Steps 7-8. MS (ES,m/z): [M+1]⁺=5713.

Example 12 Synthesis of(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((6aS,8S)-8-(((R)-tetrahydrofuran-3-yl)oxy)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)methanol

The title compound was synthesized from (3S)-oxolan-3-yl4-methylbenzenesulfonate by proceeding analogously as described inExample 11. MS (ES, m/z): [M+1]⁺=5713.

Example 13 Synthesis of(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((6aS,8S)-8-(oxetan-3-yloxy)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)methanol

Step 1:(6aS,8R)-4-iodo-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-8-yltrifluoromethanesulfonate

To a stirred solution of(6aS,8R)-4-iodo-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]-pyrrolo[1,2-d][1,4]oxazin-8-ol(400 mg, 1.257 mmol, 1.00 equiv) and DIEA (244 mg, 1.886 mmd, 1.50equiv) in DCM (4.00 mL) was added Tf₂O (426 mg, 1.509 mmol, 1.20 equiv)dropwise at 5° C. The reaction solution was stirred at 5° C. for 30 minand then concentrated under vacuum. The residue was purified by silicagel column chromatography, eluted with EtOAc/PE (0-40%) to afford thetitle compound (300 mg, 53.0%) as a white solid.

Step 2:(6aS,8S)-4-iodo-8-(oxetan-3-yloxy)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine

To a stirred solution of oxetan-3-ol (99 mg, 1.336 mmol, 2.00 equiv) inDMF (3.00 mL) was added 60% NaH (67 mg, 1.67 mmol, 2.50 equiv) at 5° C.The mixture was stirred at this temperature for 1 h.(6aS,8R)-4-Iodo-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-8-yltrifluoromethanesulfonate (300.00 mg, 0.666 mmol, 1.00 equiv) was addedat 20° C. The resulting mixture was allowed to warm to 50° C. andstirred for 10 min. The reaction was quenched with water at 5° C. andthe resulting mixture was extracted with EtOAc. The combined organiclayers were washed with water and brine, dried over anhydrous Na₂SO₄.After filtration, the filtrate was concentrated under reduced pressure.The residue was purified by silica gel column chromatography, elutedwith EtOAc/PE (0-100%) to afford the title compound (20 mg, 8.0%) as awhite solid.

Step 3:(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((6aS,8S)-8-(oxetan-3-yloxy)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)methanol

The title compound was synthesized by proceeding analogously asdescribed in Example 5 Steps 7-8 using(6aS,8S)-4-iodo-8-(oxetan-3-yloxy)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazinein Step 7. MS (ES, m/z): [M+1]⁺=557.3.

Example 14 Synthesis of(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((6aS,8S)-8-(methoxymethoxy)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)methanol

Step 1:(6aS,8S)-4-iodo-8-(methoxymethoxy)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine

To a stirred solution of(6aS,8S)-4-iodo-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d]-[1,4]oxazin-8-ol(60 mg, 0.189 mmol, 1.00 equiv) and DIEA (49 mg, 0.377 mmol, 2.00 equiv)in DME (1.00 mL) was added bromo(methoxy)methane (3535 mg, 0.283 mmol,1.50 equiv) dropwise at room temperature under N2 atmosphere. Theresulting mixture was stirred for 4 h at room temperature under N₂atmosphere and then quenched with H₂O. The resulting mixture wasextracted with EA and the combined organic layers were dried overanhydrous Na₂SO₄. After filtration, the filtrate was concentrated underreduced pressure. The residue was purified by silica gel columnchromatography, eluted with PE/EA (1/1) to afford the title compound (50mg, 73.2%) as a light yellow solid.

Step 2:(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((6aS,8S)-8-(methoxymethoxy)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)methanol

The title compound was synthesized by proceeding analogously asdescribed in Example 5 Steps 7-8 using tert-butyl((3S,4S)-8-(3-(hydroxymethyl)-5-(((6aS,8S)-8-(methoxymethoxy)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamatein Step 7. MS (ES, m/z): [M+1]⁺=5452.

Example 15 Synthesis of(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((6aS,8S)-8-(2-methoxyethoxy)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)methanol

The title compound was synthesized by proceeding analogously asdescribed in Example 14 using 2-bromoethyl methyl ether in Step 1. MS(ES, m/z): [M+1]⁺=559.3.

Example 16 Synthesis of(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((6aS,8S)-8-(cyclopropylmethoxy)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)methanol

The title compound was synthesized by proceeding analogously asdescribed in Example 14 using (bromomethyl)cyclopropane r in Step 1. MS(ES, m/z): [M+1]⁺=555.4.

Example 17 Synthesis of(3-((3S,4S)-4-amino-3-methyl-2-oxa-4-azaspiro[4.5]decan-8-yl)-6-(((S)-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin]-4′-yl)thio)pyrazin-2-yl)methanol

Step 1:(S)-4′-iodo-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[3,2-b]pyrrolo[1,2-d]-[1,4]oxazine]

Compound(S)-4′-iodo-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine]was synthesized by proceeding analogously as described in Example 1,Steps 1-4 using 5-tert-butyl 6-methyl(6S)-5-azaspiro[2.4]heptane-5,6-dicarboxylate in Step 1.

Step 2:(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((S)-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin]-4′-yl)thio)pyrazin-2-yl)methanol

The title compound was synthesized by proceeding analogously asdescribed in Example 1, Steps 5-8.MS (ES, m/z): [M+1]¹-51.3.

Example 18 and 19 Synthesis of(6aS,8S)-4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-&(hydroxymethyl)pyrazin-2-yl)thio)-8-methyl-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]-pyrrolo[1,2-d][1,4]oxazin-8-oland(6aS,8R)-4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-8-methyl-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-8-ol

stereochemistry of the tertiary alcohol arbitrarily assigned in 18 and19

Step 1:(S)-4-iodo-6a,7-dihydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-8(9H)-one

To a stirred solution of oxalyl chloride (209.47 mg, 1.650 mmol, 1.5equiv) in DCM (1.4 mL) was added DMSO (257.89 mg, 3.301 mmol, 3.0 equiv)in DCM (0.2 mL) dropwise at −78° C. under nitrogen atmosphere andstirred at this temperature for 30 min. To the above solution was addeda solution of(6aS)-4-iodo-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-8-ol(350.00 mg, 1.100 mmol, 1.00 equiv) in DCM (2.0 mL) at −78° C. Afterstirring at −78° C. for 30 min, DIEA (853.1 mg, 6.6 mmol, 6.0 equiv) wasadded dropwise at −78° C. The resulting mixture was stirred foradditional 30 min at −78° C., then warmed to room temperature over 30min. After stirring at rt for 10 min, the reaction mixture was cooled to5° C. and quenched by addition of sat. NH₄Cl aq. solution at 5° C. Theresulting mixture was extracted with EtOAc and the combined organiclayers were washed with brine, dried over anhydrous Na₂SO₄ andconcentrated to afford the title compound (250 mg, 71.8%).

Step 2: 2-ethylhexyl3-(((S)-8-oxo-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]-oxazin-4-yl)thio)propanoate

A solution of(S)-4-iodo-6a,7-dihydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-8(9H)-one(220.00 mg, 0.696 mmol, 1.00 equiv), 2-ethylhexyl 3-sulfanylpropanoate(182.37 mg, 0.835 mmol, 1.20 equiv), Pd₂(dba)₃ (63.73 mg, 0.070 mmol,0.10 equiv), XantPhos (40.27 mg, 0.070 mmd, 0.10 equiv) and DIEA (269.85mg, 2.088 mmol, 3.00 equiv) in dioxane (4.40 mL) was stirred for 1 h at100° C. under nitrogen atmosphere. The resulting mixture wasconcentrated under vacuum and the residue was purified by silica gelcolumn chromatography, eluted with EtOAc/PE (0-50%), to afford the titlecompound (280 mg, 99%).

Step 3: 2-ethylhexyl3-(((6aS)-8-hydroxy-8-methyl-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]-pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)propanoate

To a stirred solution of 2-ethylhexyl3-(((S)-8-oxo-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)propanoate(160 mg, 0.394 mmol, 1.00 equiv) in THF (1.60 mL) was added 2.0 Mbromo(methyl)magnesium (0.24 mL, 0.48 mmd, 1.22 equiv) dropwise at 5° C.under nitrogen atmosphere and the resulting mixture was stirred at 5° C.for 1 h. The reaction was quenched by addition of sat. NH₄Cl aq.solution at 5° C. and extracted with EtOAc. The combined organic layerswere washed with brine, dried over anhydrous Na₂SO₄ and concentrated.The residue was purified by silica gel column chromatography, elutedwith EtOAc/PE (0-100%), to afford the title compound (90 mg, 54.1%).

Step 4:(6aS,8S)-4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-8-methyl-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]-pyrrolo[1,2-d][1,4]oxazin-8-oland(6aS,8R)-4-((5-((3S,4S)-4-amino-3-ethyl-2-ox-8-azaspiro[4.5]decan-8-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-8-methyl-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-8-ol

The title compounds were synthesized from 2-ethylhexyl3-(((6aS)-8-hydroxy-8-methyl-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)propanoateby proceeding analogously as described in Example 1, Steps 6-8. MS (ES,m/z):[M+1]⁺=515.3.

Example 20 Synthesis of(6aS,8S)-4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine-8-carbonitrile

Step 1:(6aS,8R)-4-iodo-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-8-ylmethanesulfonate

To a stirred solution of(6aS,8R)-4-iodo-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-8-ol(400.00 mg, 1.257 mmol, 1.00 equiv) in DCM (6.00 mL) were added TEA(190.86 mg, 1.886 mmol, 1.50 equiv) and MsCl (172.85 mg, 1.509 mmol,1.20 equiv) at room temperature. After stirring for 16 h at roomtemperature, the reaction mixture was cooled to 0° C. and quenched withwater. The resulting mixture was extracted with EtOAc and the combinedorganic layers were washed with brine, dried over anhydrous Na₂SO₄ andconcentrated. The residue was purified by silica gel columnchromatography, eluted with EtOAc/PE (0-50%) to afford the titlecompound (450 mg, 90.3%).

Step 2:(6aS,8S)-4-iodo-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2d][1,4]oxazine-8-carbonitrile

To a stirred solution of(6aS,8R)-4-iodo-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-8-ylmethanesulfonate (300.00 mg, 0.757 mmol, 1.00 equiv) in DMF (5.00 mL)was added NaCN (55.66 mg, 1.136 mmol, 1.50 equiv) at room temperature.After stirring at 75° C. for 16 h, the reaction mixture was cooled atroom temperature and quenched with water. The mixture was then extractedwith EtOAc and the combined organic layers were washed with brine, driedover anhydrous Na₂SO₄ and concentrated. The residue was purified bysilica gel column chromatography, eluted with EtOAc/PE (0-50%), toafford the title compound (140 mg, 56.5%).

Step 3: (6aS,8S)-4-((5-((3S,4S)-4-amino-3-methyl-2oxa-8-azaspiro[4.5]decan-8-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]-oxazine-8-carbonitrile

The compound was synthesized from(6aS,8S)-4-iodo-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine-8-carbonitrileby proceeding analogously as described in Example 5, Steps 7-8.[M+1]⁺=510.2.

Example 21 Synthesis of(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((6aS,8S)-8-(methylsulfonyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)methanol

Step 1: 1-tert-butyl 2-methyl(2S,4R)-4-(methanesulfonyloxy)pyrrolidine-1,2-dicarboxylate

To a stirred solution of 1-tert-butyl 2-methyl(2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (9 g, 36.7 mmol, 1.0equiv) and TEA (7.43 g, 73.4 mmol, 2.0 equiv) in DCM (100 mL) was addedMsCl (5 g, 43.6 mmol, 1.2 equiv) dropwise at 0° C. and the resultingmixture was stirred for 1 h at 0° C. The reaction was quenched withwater and extracted with DCM. The combined organic layers were washedwith water and brine, dried over anhydrous Na₂SO₄ and concentrated. Theresidue was purified by silica gel column chromatography, eluted withEtOAc/PE (0-50%), to afford the title compound (10.5 g, 88.5%).

Step 2: 1-(tert-butyl) 2-methyl(2R,4R)-4-methoxypyrrolidine-1,2-dicarboxylate

A solution of 1-tert-butyl 2-methyl(2S,4R)-4-(methanesulfonyloxy)pyrrolidine-1,2-dicarboxylate (4.30 g,13.298 mmol, 1.00 equiv) in dry DMF (20.00 mL) was added NaSCH₃ (1.07 g,15.27 mmol, 1.07 equiv) at 30° C. After stirring overnight at rt, thereaction mixture was poured into water and extracted with EtOAc. Thecombined organic layers were washed with water and brine, dried overNa₂SO₄ and concentrated. The residue was purified by silica gel columnchromatography, eluted with PE/EA (1/1) to afford the title compound (4g, 109.2%).

Step 3: tert-butyl(2S,4S)-2-(hydroxymethyl)-4-(methylthio)pyrrolidine-1-carboxylate

To a stirred mixture of 1-tert-butyl 2-methyl(2S,4S)-4-(methylsulfanyl)pyrolidine-1,2-dicarboxylate (3.70 g, 13.44mmol, 1.0 equiv) in THF (37.0 mL) was added LiAlH₄ (0.76 g, 20.03 mmol,1.5 equiv) in portions at 0° C. After stirring at room temperature for 2h, the reaction mixture was quenched with Na₂SO₄·10H₂O at roomtemperature. The resulting mixture was filtered and the filtrate wasconcentrated under reduced pressure to give the title compound (2.6 g,78.2%).

Step 4: tert-butyl(2S,4S)-2-(hydroxymethyl)-4-(methylsulfonyl)pyrrolidine-1-carboxylate

To a stirred solution of tert-butyl(2S,4S)-2-(hydroxymethyl)-4-(methylsulfanyl)-pyrrolidine-1-carboxylate(3.70 g, 14.959 mmol, 1.00 equiv) in DCM (40 mL) at room temperature wasadded m-CPBA (77%12.91 g, 57.60 mmol, 3.85 equiv) in portions over 5 h.The resulting mixture was diluted with DCM and washed with sat. aq.NaHCO₃ solution and brine, dried over anhydrous Na₂SO₄ and concentrated.The residue was purified by silica gel column chromatography, elutedwith DCM/MeOH (20/1), to afford the title compound (1 g, 23.9%).

Step 5:(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((6aS,8S)-8-(methylsulfonyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)methanol

The title compound was synthesizedtert-butyl(2S,4S)-2-(hydroxymethyl)-4-(methylsulfonyl)pyrrolidine-1-carboxylateby the method described in Example 1, Steps 2-8. MS (ES, m/z):[M+1]⁺=563.3.

Example 22 Synthesis of(6aS,8S)-4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(hydroxymethyl)pyrazine-2-yl)thio)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d]-[1,4]oxazin-8-ylcarbamate

Step 1:(6aS,8S)-4-iodo-6a,7,8,9-tetrahydro-6H-pyrid[3,2-b]pyrrolo[1,2-d][1,4]oxazin-8-ylcarbamate

To a stirred solution of(6aS,8S)-4-iodo-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-8-ol(150.0 mg, 0.472 mmol, 1.0 equiv) in DCM (1.80 mL) was addedtrichloroethanecarbonyl isocyanate (222.08 mg, 1.179 mmol, 2.5 equiv)dropwise at 5° C. and the resulting mixture was stirred at thistemperature for about 30 min. To the above solution, K₂CO₃ (129.88 mg,0.940 mmol, 2.0 equiv) and MeOH (1.80 mL) were added at room temperatureand the resulting mixture was stirred for additional 6 h at roomtemperature. The mixture was diluted with water and extracted withEtOAc. The combined organic layers were washed with brine, dried overanhydrous Na₂SO₄ and concentrated. The residue was purified by silicagel column chromatography, eluted with EtOAc/PE (0-100%) to afford thetitle compound (100 mg, 58.7%).

Step 2:(6aS,8S)-4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]-oxazin-8-ylcarbamate

The title compound was synthesized fromtert-butyl(2S,4S)-2-(hydroxymethyl)-4-(methylsulfonyl)pyrrolidine-1-carboxylateby proceeding analogously as described in Example 5, Steps 7-8. MS (ES,m/z): [M+1]⁺=544.3.

Example 23 Synthesis of(6aS,8R)-4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-8-ylcarbamate

The title compound was synthesized from((6aS,8R)-4-iodo-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-8-olby as described in example 22. MS (ES, m/z): [M+1]⁺=544.2.

Example 24 Synthesis of(6-(((6aS,8S)-8-(H-pyrazol-1-yl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]-pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)-3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)methanol

Step 1:(6aS,8S)-4-iodo-8-(1H-pyrazol-1-yl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]-pyrrolo[1,2-d][1,4]oxazine

To a stirred solution of pyrazole (17.18 mg, 0.252 mmol, 1.0 equiv) inDMF (0.75 mL) was added NaH (20.19 mg, 0.505 mmol, 2.0 equiv, 60%) inportions at 5° C. and the resulting mixture was stirred at 5° C. for 1h. To the above mixture was added(6aS,8R)-4-iodo-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-8-ylmethanesulfonate (100.00 mg, 0.252 mmol, 1.00 equiv) at room temperatureand the resulting mixture was stirred at 50° C. After cooling to 0° C.,the reaction was quenched by addition of water and then extracted withEtOAc. The combined organic layers were washed with water, brine, driedover anhydrous Na₂SO₄ and concentrated. The residue was purified bysilica gel column chromatography, eluted with EtOAc/PE (0-100%), toafford the title compound (60 mg, 64.5%).

Step 2:(6-(((6aS,8S)-8-(1H-pyrazol-1-yl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)-3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)methanol

The title compound was synthesized from(6aS,8S)-4-iodo-8-(1H-pyrazol-1-yl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazineby proceeding analogously described in Example 5, Steps 7-8. MS (ES,m/z):[M+1]⁺=551.3

Example 25 Synthesis of(6-(((6aS,8R)-8-(1H-pyrazol-1-yl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]-pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)-3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)methanol

The title compound was synthesized from(6aS,8S)-4-iodo-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-8-ylmethanesulfonate by the method described in Example 24. MS (ES, m/z):[M+1]⁺=551.3.

Example 26 and 27 Synthesis of(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((R)-6a,7,9,10-tetrahydro-6H-[1,4]oxazino[4,3-d]pyrido[3,2-b][1,4]oxazin-4-yl)thio)pyrazin-2-yl)methanoland(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((S)-6a,7,9,10-tetrahydro-6H-[1,4]oxazino[4,3-d]pyrido[3,2-b][1,4]oxazin-4-yl)thio)pyrazin-2-yl)methanol

The title compounds were synthesized by proceeding analogously asdescribed in Example 5, Steps 2-8 using tert-butyl3-(hydroxymethyl)morpholine-4-carboxylate in Step 2. MS (ES, m/z):[M+1]⁺=501.2.

Example 28 Synthesis of4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl-6-(hydroxymethyl)pyrazin-2-yl)thio)-6a,7,9,10-tetrahydro-6H-pyrido[3,2-b][,4]thiazino[4,3-d][1,4]oxazine8,8-dioxide

Step 1: 4-(tert-butoxycarbonyl)thiomorpholine-3-carboxylic acid

To a stirred solution of thiomorpholine-3-carboxylic acid (3000 mg,20.382 mmol, 1.00 equiv) and Et₃N (4125 mg, 40.764 mmol, 2.00 equiv) inDCM (50.00 mL) was added Boc₂O (6672 mg, 30.57 mmol, 1.50 equiv) inportions at room temperature under N2 atmosphere. The resulting mixturewas stirred for 16 h at room temperature under N₂ atmosphere and thendiluted with water and extracted with DCM. The combined organic layerswere dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by silica gel column chromatography, eluted with DCM/MeOH(10/1) to afford the title compound (3.2 g, 63.5%) as light yellow oil.

Step 2: tert-butyl 3-(hydroxymethyl)thiomorpholine-4-carboxylate

To a stirred solution of4-(tert-butoxycarbonyl)thiomorpholine-3-carboxylic acid (2000 mg, 8.087mmol, 1.00 equiv) in THF (20 mL) was added 1M BH₃-THF (16.18 mL, 16.180mmol, 2.00 equiv) dropwise at 0° C. under N2 atmosphere. The resultingmixture was stirred for 16 h at 45° C. under N2 atmosphere and thenquenched with MeOH at 0° C. The resulting mixture was concentrated undervacuum and the residue was purified by silica gel column chromatography,eluted with DCM/MeOH (10/1) to afford the title compound (1.8 g, 95.4%)as light yellow oil.

Step 3: tert-butyl 3-(hydroxymethyl)thiomorpholine-4-carboxylate1,1-dioxide

A solution of tert-butyl 3-(hydroxymethyl)thiomorpholine-4-carboxylate(500 mg, 2.143 mmol, 1.00 equiv) and m-CPBA (77%, 851 mg, 3.78 mmol,1.77 equiv) in DCM (10 mL) was stirred for 16 h at room temperatureunder N2 atmosphere. The reaction was quenched with saturated NaHCO₃(5mL) at room temperature. The resulting mixture was extracted with DC.The combined organic layers were washed with saturated NaHCO₃, driedover anhydrous Na₂SO₄. After filtration, the filtrate was concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography, eluted with DCM/MeOH (10/1) to afford the title compound(400 mg, 70.4%) as light yellow oil.

Step 4: 3-(hydroxymethyl)thiomorpholine 1,1-dioxide; trifluoroaceticacid

To a stirred solution of tert-butyl3-(hydroxymethyl)thiomorpholine-4-carboxylate 1,1-dioxide (180 mg, 0.678mmol, 1.00 equiv) in DCM (5.0 mL) was added TFA (3.868 g, 33.921 mmd,50.00 equiv) at room temperature. The resulting mixture was stirred for2 h at room temperature. The resulting mixture was concentrated underreduced pressure to afford the title compound (170 mg, 89.74%) as awhite solid.

Step5:4-iodo-6a,7,9,10-tetrahydro-6H-pyrido[3,2-b][1,4]thiazino[4,3-d][1,4]oxazine8,8-dioxide

To a stirred solution of 3-(hydroxymethyl)thiomorpholine 1,1-dioxidetrifluoroacetic acid (180 mg, 0.645 mmol, 1.00 equiv) and2-fluoro-4-iodopyridin-3-ol (154 mg, 0.645 mmol, 1.00 equiv) in toluene(3.0 mL) were added PPh₃ (254 mg, 0.967 mmol, 1.50 equiv) and DEAD (168mg, 0.967 mmol, 1.50 equiv) at room temperature under nitrogenatmosphere. The resulting mixture was stirred for 16 h at 60° C. undernitrogen atmosphere and then concentrated under reduced pressure. Theresidue was purified by Prep-TLC (PE/EtOAc 5:1) to afford the titlecompound (45 mg, 19.1%) as a light yellow solid.

Step 6:4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(hydroxymethyl)-pyrazin-2-yl)thio)-4a,7,9,10-tetrahydro-6H-pyrido[3,2-b][1,4]thiazino[4,3-d][1,4]oxazine8,8-dioxide

The title compounds were synthesized by proceeding analogously asdescribed in Example 5, Steps 7-8 using4-iodo-6a,7,9,10-tetrahydro-6H-pyrido[3,2-b][1,4]thiazino[4,3-d][1,4]oxazine8,8-dioxide in Step 7. MS (ES, m/z): [M+1]⁺=549.2.

Example 29 and 30 Synthesis of(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((6aS,8S)-8-(methoxymethyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)methanol[29] and(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((6aS,8R)-8-(methoxymethyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)methanol[30]

Step 1: 1-(tert-butyl) 2-methyl(S)-4-(methoxymethylene)pyrrolidine-1,2-dicarboxylate

To a stirred mixture of 1-(tert-butyl) 2-methyl(S)-4-oxopyrrolidine-1,2-dicarboxylate (4.00 g, 16.443 mmol, 1.00 equiv)and K₂CO₃ (1.50 g, 10.853 mmol, 0.66 equiv) in MeOH (80.0 mL) was addeddimethyl (1-diazo-2-oxopropyl)phosphonate (9.48 g, 49330 mmol, 3.00equiv) at 0° C. under nitrogen atmosphere. After stirring for 12 h atroom temperature, the reaction mixture was poured into water and theresulting mixture was extracted with EtOAc. The organic layer was washedwith brine, dried over anhydrous Na₂SO₄ and concentrated. The residuewas purified by silica gel column chromatography, eluted with PE/EtOAc(3:1), to afford the title compound (1.45 g, 32.5%) as a light-yellowoil.

Step 2: 1-(tert-butyl) 2-methyl(2S)-4-(methoxymethyl)pyrrolidine-1,2-dicarboxylate

To a stirred solution of 1-(tert-butyl)2-methyl(S)-4-(methoxymethylene)pyrrolidine-1,2-dicarboxylate (1.45 g, 5.344mmol, 1.00 equiv) and 10% Pd/C (145 mg) in MeOH (20.0 mL) was added MgO(220 mg, 5.46 mmol, 1.02 equiv) at room temperature under hydrogenatmosphere. After stirring for 2 h at room temperature, the resultingmixture was filtered. The filtrate was concentrated under reducedpressure to afford the title compound (1.35 g, 92.42%) as a light-yellowoil which was used directly in next step without any furtherpurification.

Step 3:tert-butyl(2S)-2-(hydroxymethyl)-4-(methoxymethyl)pyrrolidine-1-carboxylate

To a stirred solution of 1-(tert-butyl) 2-methy(2S)-4-(methoxymethyl)pyrrolidino-1,2-dicarboxylate (180 mg, 0.659 mmol,1.00 equiv) in THF (4.0 mL) was added LiAlH₄ (37 mg, 0.975 mmol, 1.50equiv) at room temperature. After stirring for 2 h at room temperature,the resulting mixture was diluted with DCM and quenched with water at 0°C. After filtration, the filter cake was washed with DCM. The organiclayer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated. The residue was purified by silica gel columnchromatography, eluted with PE/EtOAc (1:1) to afford the title compound(90 mg, 55.7%) as a light-yellow oil.

Step 4: tert-butyl(2S)-2-(((2-fluoro-4-iodopyridin-3-yl)oxy)methyl)-4-(methoxymethyl)-pyrrolidine-1-carboxylate

To a stirred solution of tert-butyl(2S)-2-(hydroxymethyl)-4-(methoxymethyl)-pyrrolidine-1-carboxylate (90mg, 0.367 mmol, 1.00 equiv) and 2-fluoro-4-iodopyridin-3-ol (88 mg,0.367 mmol, 1.00 equiv) in THF (2.00 mL) were added PPh₃ (144 mg, 0.550mmol, 1.50 equiv) and DEAD (96 mg, 0.55 mmol, 1.50 equiv) at roomtemperature under nitrogen atmosphere. After stirring for 16 h at roomtemperature, the reaction mixture was concentrated under reducedpressure. The residue was purified by silica gel column chromatography,eluted with EtOAc/PE (0-60%) to afford the title compound (115 mg,67.2%) as a light-yellow oil.

Step 5:2-fluoro-4-iodo-3-(((2S)-4-(methoxymethyl)pyrrolidin-2-yl)methoxy)pyridinehydrogen chloride

To a stirred solution of tert-butyl(2S)-2-(((2-fluoro-4-iodopyridin-3-yl)oxy)methyl)-4-(methoxymethyl)pyrrolidine-1-carboxylate(115 mg, 0.247 mmol, 1.00 equiv) in dioxane (1.0 mL) was added HCl (4.0M in dioxane, 0.62 mL, 2.48 mmol, 10.00 equiv) at room temperature.After stirring for 5 h at room temperature, the reaction mixture wasconcentrated under reduced pressure to afford the title compound (110mg, crude) as a light yellow solid, which was used directly in next stepwithout further purification. MS (ES, m/z): [M+1]⁺=367.0.

Step 6:(6aS)-4-iodo-8-(methoxymethyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine

To a stirred solution of2-fluoro-4-iodo-3-(((2S,4S)-4-(methoxymethyl)pyrrolidin-2-yl)-methoxy)pyridinehydrogen chloride (110 mg, 0.273 mmol, 1.00 equiv) in EtOH (3.0 mL) wasadded K₂CO₃ (208 mg, 1.50 mmol, 5.51 equiv) at room temperature. Afterstirring for 2 h at 60° C., the reaction mixture was concentrated underreduced pressure. The residue was purified by silica gel columnchromatography, eluted with EtOAc/PE (0-60%) to afford the titlecompound (80 mg, 2 steps 93.5%) as a light-yellow oil.

Step 7: tert-butyl((3S,4S)-8-(3-(hydroxymethyl)-5-(((6aS)-8-(methoxymethyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate

To a stirred mixture of(6aS)-4-iodo-8-(methoxymethyl)-6a,7,8,9-tetrahydro-6H-pyrido-[3,2-b]pyrrolo[1,2-d][1,4]oxazine(80 mg, 0.231 mmol, 1.00 equiv), sodium5-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(hydroxy-methyl)pyrazine-2-thiolate(100 mg, 0.231 mmol, 1.0 equiv), Pd₂(dba)₃ (63 mg, 0.069 mmol, 0.30equiv) and XantPhos (40 mg, 0.069 mmol, 0.30 equiv) in dioxane (1.50 mL)was added DIEA (90 mg, 0.693 mmol, 3.00 equiv) at room temperature undernitrogen atmosphere. After stirring for 1 h at 80° C., the reactionmixture was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography, eluted with MeOH/DCM(0-10%) to afford the title compound (110 mg, 75.7%) as a yellow solid.

Step 8:(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((6aS,8S)-8-(methoxymethyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)-pyrazin-2-yl)methanol1291 and(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((6aS,8R)-8-(methoxymethyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)methanol[30]

To a stirred solution oftert-butyl((3S,4S)-8-(3-(hydroxymethyl)-5-(((6aS,8S)-8-(methoxymethyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)-pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate(70.00 mg, 0.111 mmol, 1.00 equiv) in DCM (1.0 mL) was added TFA (0.20mL, 2.61 mmol, 23.5 equiv) at room temperature. After stirring for 2 hat room temperature, the reaction mixture was concentrated under reducedpressure. The mixture was purified by Prep-HPLC to afford 50 mg of crudeproduct. The crude product (50 mg) was further purified by Chiral-HPLCto afford the title compound 1291(9.9 mg, 16.8%), MS (ES, m/z):[M+1]=529.3 and [30] (5.5 mg, 9.4%), MS (ES, m/z): [M+1]⁺=529.3; as awhite solid.

Example 31 Synthesis of(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((6aS,8S)-8-((methoxymethoxy)methyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)methanol

Step 1:tert-butyl(2S,4S)-2-(hydroxymethyl)-4-(methoxymethyl)pyrrolidine-1-carboxylate

To a stirred solution of(2S,4S)-1-(tert-butoxycarbonyl)-4-(methoxymethyl)pyrrolidine-2-carboxylicacid (180 g, 694.171 mmol, 1.00 equiv) in THF (1.8 L) was added BH₃—Me₂S(173.00 mL, 1824.073 mmol, 2.63 equiv) dropwise at 0° C. under N2atmosphere. The resulting mixture was stirred for 16 h at roomtemperature under N2 atmosphere. The reaction was quenched with MeOH(200 mL) at 0° C. and the resulting mixture was concentrated underreduced pressure. The residue was purified by silica gel columnchromatography, eluted with PE/EA (1/1), to afford the title compound(160 g, 94%) as a colorless oil.

Step 2:tert-butyl(2S,4S)-2-(((2-fluoro-4-iodopyridin-3-yl)oxy)methyl)-4-(methoxymethyl)-pyrrolidine-1-carboxylate

To a stirred solution of tert-butyl(2S,4S)-2-(hydroxymethyl)-4-(methoxymethyl)-pyrrolidine-1-carboxylate(7.0 g, 28.534 mmol, 1.00 equiv), 2-fluoro-4-iodopyridin-3-od (6.8 g,28.534 mmol, 1.00 equiv) and PPh₃ (11.2 g, 42.7 mmol, 1.50 equiv) in THF(140.00 mL) was added DEAD (7.5 g, 43 mmol, 1.5 equiv) dropwise at rtunder N2 atmosphere and the resulting mixture was stirred for 16 h atroom temperature. The reaction mixture was then concentrated underreduced pressure and the residue was purified by silica gel columnchromatography, eluted with PE/EA (5/1), to afford the title compound(11.5 g, 86.4%) as a light-yellow oil.

Step 3:2-fluoro-4-iodo-3-(((2S,4S)-4-(methoxymethyl)pyrrolidin-2-yl)methoxy)pyridinedihydrochloride

A solution of tert-butyl(2S,4S)-2-(((2-fluoro-4-iodopyridin-3-yl)oxy)methyl)-4-(methoxymethyl)pyrrolidine-1-carboxylate(11.5 g, 24.663 mmol, 1.00 equiv) in 1,4-dioxane (20.0 mL) and 4.0 M HClin 1,4-dioxane (50.0 mL) was stirred for 3 h at room temperature underN₂ atmosphere. The resulting mixture was concentrated under reducedpressure to afford the title compound (14 g, crude) as a light-yellowoil, which was used for next step without further purification.

Step 4:(6aS,8S)-4-iodo-8-(methoxymethyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine

A mixture of crude2-fluoro-4-iodo-3-(((2S,4S)-4-(methoxymethyl)pyrrolidin-2-yl)-methoxy)pyridinedihydrochloride (14.0 g, 31.88 mmol, 1.00 equiv) and K₂CO₃ (15.9 g, 115mmol, 3.6 equiv) in EtOH (280.0 mL) was stirred for 3 h at 60° C. Aftercooled at rt, the resulting mixture was filtered and the filter cake waswashed with EtOAc. The combined filtrate was concentrated under reducedpressure. The residue was purified by silica gel column chromatography,eluted with PE/EA (2/1), to afford the title compound (6.6 g, 2 steps77%) as a light yellow solid.

Step 5:((6aS,8S)-4-iodo-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-8-yl)-methanol

To a stirred mixture of(6aS,8S)-4-iodo-8-(methoxymethyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine (250 mg, 0.722 mmol, 1.00 equiv) and NaI (357 mg,2.383 mmol, 3.3 equiv) in CH₃CN (5.00 mL) was added SiCl₄ (405 mg, 2.383mmol, 3.30 equiv) dropwise at room temperature under nitrogenatmosphere. The resulting mixture was stirred for 2 h at 80° C. undernitrogen atmosphere. The mixture was allowed to cool to roomtemperature, diluted with water, and the pH of the solution was adjustedto pH=8 with saturated NaHCO₃ aq solution. The resulting mixture wasextracted with DCM and the organic layer was dried over anhydrous Na₂SO₄and concentrated. The residue was purified by silica gel columnchromatography, eluted with PE/EtOAc (1:1), to afford the title compound(200 mg, 83.4%) as a yellow solid.

Step 6:(6aS,8S)-4-iodo-8-((methoxymethoxy)methy)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine

To a stirred solution of((6aS,8S)-4-iodo-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-8-yl)methanol(75 mg, 0.226 mmol, 1.00 equiv) and DIEA (88 mg, 0.68 mmol, 3.0 equiv)in DCM (3.75 mL) was added bromo(methoxy)methane (85 mg, 0.68 mmol, 3.0equiv) dropwise at room temperature under nitrogen atmosphere. Theresulting mixture was stirred for 24 h at room temperature undernitrogen atmosphere. The reaction solution was purified by silica gelcolumn chromatography, eluted with PE/EtOAc (1:1), to afford the titlecompound (65 mg, 76.5%) as a yellow solid.

Step 7: tert-butyl((3S,4S)-8-(3-(hydroxymethyl)-5-(((6aS,8S)-8-((methoxymethoxy)methyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate

To a stirred mixture of sodium5-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(hydroxymethyl)pyrazine-2-thiolate (55 mg, 0.127 mmol,1.00 equiv),(6aS,8S)-4-iodo-8-((methoxymethoxy)methyl)-6a7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine(48 mg, 0.128 mmol, 1 equiv) and XantPhos (22 mg, 0.038 mmol, 0.30equiv) in dioxane (2.0 mL) were added DIEA (82 mg, 0.63 mmol, 5 equiv)and Pd₂(dba)₃ (35 mg, 0.038 mmol, 0.30 equiv) in portions at roomtemperature under nitrogen atmosphere. The resulting mixture was stirredfor 1 h at 80° C. under nitrogen atmosphere and then diluted with waterand extracted with EtOAc. The organic layer was dried over anhydrousNa₂SO₄. After filtration, the filtrate was concentrated under reducedpressure and the residue was purified by silica gel columnchromatography, eluted with DCM/MeOH (10:1), to afford the titlecompound (45 mg, 53.8%) as a brown solid.

Step 8:(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-64-((6aS,8S)-8-((methoxymethoxy)methyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)methanol

To a stirred solution of tert-butyl((3S,4S)-8-(3-(hydroxymethyl)-5-(((6aS,8S)-8-(methoxy-methoxy)methyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)-pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate(35 mg, 0.053 mmol, 1.00 equiv) in DCM (1.80 mL) was added dropwise TFA(0.15 mL) at room temperature. The resulting mixture was stirred for 2 hat room temperature and then basified to pH=8 with ammonia hydroxide aq.solution. The organic solvent was removed under vacuum and the residuewas purified by Prep-HPLC to afford the title compound (7 mg, 23.6%) asa white solid. MS (ES, m/z): [M+1]⁺=559.3.

Example 32 Synthesis of(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((6aS,8S)-8-((2-methoxyethoxy)methyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)methanol

The title compound was synthesized by proceeding analogously asdescribed in Example 31, Steps 6-8 using 1-bromo-2-methoxyethane in Step6. MS (ES, m/z): [M+1]⁺=573.3.

Example 33 Synthesis of(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((6aS,8S)-8-((cyclopropylmethoxy)methyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)methanol

The title compound was synthesized by proceeding analogously asdescribed in Example 31, Steps 6-8 using (bromomethyl)cyclopropane inStep 6. MS (ES, m/z): [M+1]⁺=569.3

Example 34 Synthesis of(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((6aS,8S)-8-((oxetan-3-ylmethoxy)methyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)methanol

The title compound was synthesized by proceeding analogously asdescribed in Example 31, Steps 6-8 using 3-(bromomethyl)oxetane in Step6. MS (ES, m/z): [M+1]⁺=585.3

Example 35 Synthesis of formic acid;(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((S)-2-amino-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)methanol

Step 1: 2-fluoro-4-iodo-6-nitropyridin-3-ol

To a stirred solution of 2-fluoro-4-iodopyridin-3-ol (100 mg, 0.418mmol, 1.00 equiv) and Bu₄NNO₃ (191 mg, 0.628 mmol, 1.50 equiv) in DCM(2.0 mL) was added TFAA (0.10 mL, 0.595 mmol, 1.42 equiv) dropwise at 0°C. under nitrogen atmosphere and the resulting mixture was stirred for 1h at 0° C. The reaction was quenched with saturated NH₄Cl (aq.) at 0° C.and the resulting mixture was extracted with EtOAc. The combined organiclayers were washed with water and brine, dried over anhydrous Na₂SO₄.After filtration, the filtrate was concentrated under reduced pressure.The residue was purified by silica gel column chromatography, elutedwith PE/EtOAc (5:1), to afford the title compound (10 mg, 8.4%) as ayellow solid.

Step 2: tert-butyl(S)-2-(((2-fluoro-4-iodo-6-nitropyridin-3-yl)oxy)methyl)pyrrolidine-1-carboxylate

To a stirred solution of 2-fluoro-4-iodo-6-nitropyridin-3-ol (170 mg,0.599 mmol, 1.00 equiv),tert-butyl(2S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (180 mg, 0.898mmol, 1.50 equiv) and PPh₃ (235 mg, 0.9 mmol, 1.5 equiv) in THF (2 mL)was added DIAD (181 mg, 0.9 mmol, 1.5 equiv) dropwise at 0° C. undernitrogen atmosphere. The resulting mixture was stirred overnight at 60°C. under nitrogen atmosphere and then quenched with water at roomtemperature. The resulting mixture was extracted with EtOAc and thecombined organic layers were washed with water and brine, dried overanhydrous Na₂SO₄. After filtration, the filtrate was concentrated underreduced pressure. The residue was purified by silica gel columnchromatography, eluted with EtOAc/PE (0-30%) to afford the titlecompound (50 mg, 17.9%) as a yellow oil.

Step 3: (S)-2-fluoro-4-iodo-6-nitro-3-(pyrrolidin-2-ylmethoxy)pyridinehydrochloride

Into a8 mL sealed tube were addedtert-butyl(S)-2-(((2-fluoro-4-iodo-6-nitropyridin-3-yl)oxy)methyl)pyrrolidine-1-carboxylate (50 mg, 0.107 mmol, 1.00 equiv) and a solutionof 4 M HCl in 1,4-dioxane (0.50 mL, 2.0 mmol, 18.69 equiv) at 0° C. Thereaction solution was stirred for 1 h at room temperature and thenconcentrated under reduced pressure. The residue was triturated withEt₂O to give the crude title product (30 mg) as a yellow oil which wasused in the next step directly without further purification.

Step 4:(S)-4-iodo-2-nitro-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine

Into an 8 mL sealed tube were added(S)-2-fluoro-4-iodo-6-nitro-3-(pyrrolidin-2-ylmethoxy)pyridinehydrochloride (30 mg, crude), K₂CO₃ (34 mg, 0.246 mmol) and EtOH (0.30mL) at room temperature. The resulting mixture was stirred for 2 h at60° C. and then allowed to cool down to room temperature. The resultingmixture was extracted with EtOAc and the combined organic layers werewashed with water and brine, dried over anhydrous Na₂SO₄. Afterfiltration, the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography, eluted withPE/EtOAc (5:1) to afford the title compound (13 mg, 2 steps 34.6%) as ayellow solid.

Step 5:(S)-4-iodo-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-2-amine

A mixture of(S)-4-iodo-2-nitro-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine(13 mg, 0.037 mmol, 1.0 equiv), NH₄Cl (4 mg, 0.075 mmol, 2.0 equiv) andFe (4 mg, 0.075 mmol, 2.0 equiv) in EtOH (0.10 mL) and H₂O (0.10 mL) wasstirred for 2 h at 60° C. The mixture was allowed to cool down to roomtemperature and filtered. The filter cake was washed with EtOAc and thefiltrate was washed with water and brine, dried over anhydrous Na₂SO₄.After filtration, the filtrate was concentrated under reduced pressureand the residue was purified by silica gel column chromatography, elutedwith EtOAc/PE (0-100%), to afford the title compound (9 mg, 75.8%) as ayellow solid.

Step 6: formic acid;(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((S)-2-amino-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)methanol

The title compound was synthesized by proceeding analogously asdescribed in Example 5, Steps 7-8 using(S)-4-iodo-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-2-aminein Step 7. MS (ES, m/z): [M+1]¹500.3.

Example 36 and 37 Synthesis of(3-((S)-5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)-6-(((6aS,8S)-8-(methoxymethyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)methanol[36] and(3-((S)-5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)-6-(((648R)-8-(methoxymethyl)-6,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)methanol[37]

Step 1: 2-ethylhexyl3-(((6aS)-8-(methoxymethyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)propanoate

To a stirred mixture of(6aS)-4-iodo-8-(methoxymethyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine(500 mg, 1.444 mmol, 1.00 equiv), 2-ethylhexyl 3-sulfanylpropanoate (378mg, 1.733 mmol, 1.20 equiv), Pd₂(dba)₃ (130 mg, 0.142 mmol, 0.10 equiv)and XantPhos (85 mg, 0.147 mmol, 0.10 equiv) in 1,4-dioxane (7.5 mL) wasadded DIEA (560 mg, 4.333 mmol, 3.00 equiv) at room temperature undernitrogen atmosphere and the resulting mixture was stirred for 2 h at 85°C. After cooling to rt, the reaction was quenched with water andextracted with EtOAc. The combined organic layers were washed withbrine, dried over anhydrous Na₂SO₄ and concentrated and the residue waspurified by silica gel column chromatography, eluted with EtOAc/PE(0-60%), to afford the title compound (500 mg, 79.3%) as a light-yellowoil.

Step 2:sodium(6aS)-8-(methoxymethyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine-4-thiolate

To a stirred solution of 2-ethylhexyl3-(((6aS)-8-(methoxymethyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)propanoate(500 mg, 1.145 mind, 1.00 equiv) in MeOH (10.0 mL) was added NaOMe (68mg, 1.260 mmol, 1.10 equiv) at room temperature. After stirring for 5 hat room temperature, the reaction mixture was concentrated under vacuumand the residue was triturated with Et₂O to afford the title compound(220 mg, 70%) as a yellow solid.

Step 3:(3-chloro-6-(((6aS)-8-(methoxymethyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)methanol

To a stirred mixture of sodium(6aS)-8-(methoxymethyl)-6a7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine-4-thiolate(100 mg, 0.365 mmol, 1.00 equiv), (6-bromo-3-chloropyrazin-2-yl)methanol(90 mg, 0.40 mmol, 1.10 equiv), Pd₂(dba)₃ (33 mg, 0.036 mmol, 0.10equiv) and XantPhos (21 mg, 0.036 mmol, 0.10 equiv) in 1,4-dioxane (2mL) was added DIEA (141 mg, 1.09 mmol, 3.0 equiv) at room temperatureunder nitrogen atmosphere. After stirring for 2 h at 85° C., thereaction mixture was concentrated under vacuum and the residue waspurified by silica gel column chromatography, eluted with EtOAc/PE(0-60%), to afford the title compound (105 mg, 72.9%) as a light yellowoil.

Step 4:(3-((S)-5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)-6-(((6aS,8S)-8-(methoxymethyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)methanoland(3-((S)-5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)-6-(((6aS,8R)-8-(methoxymethyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyazin-2-ylmethanol

To a stirred mixture of(3-chloro-6-(((6aS)-8-(methoxymethyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)methanol(50 mg, 0.127 mmol, 1.00 equiv) and(S)-5,7-dihydrospir[cyclopena[b]pyridine-6,4′-piperidin]-5-aminetrihydrochloride (50 mg, 0.159 mmol, 1.25 equiv) in ACN (2.0 mL) wasadded DIEA (82 mg, 0.63 mmol, 5.0 equiv) at room temperature and theresulting mixture was stirred at 80° C. for 48 h. After cooling to roomtemperature, the reaction mixture was filtered and the filter cake waswashed with MeOH and the combined filtrate was concentrated and theresidue was purified by Prep-HPLC to afford the title compounds. MS (ES,m/z): [M+1]⁺=562.3.

Example 38 Synthesis of(3-((S)-5-amino-3-oxa-9-azadispiro[3.1.56.24]tridecan-9-yl)-6-(((6aS,8S)-8-(methoxymethyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)methanol

A solution of(3-chloro-6-(((6aS,8S)-8-(methoxymethyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)methanol(35 mg, 0.089 mmol, 1.00 equiv),(S)-13-oxa-9-azadispiro[3.1.5⁶.2⁴]tridecan-5-amine dihydrochloride (29mg, 0.106 mmol, 1.20 equiv) and DIEA (57 mg, 0.443 mmol, 5.00 equiv) inCH₃CN (0.56 mL) was stirred for 16 h at 80° C. The reaction mixture waspurified by Pre-HPLC to afford the title compound (9.8 mg, 18.4%) asyellow solid. MS (ES, m/z): [M+1]⁺=555.2.

Example 39 and 40 Synthesis of(3-((S)-5-amino-13-oxa-9-azadispiro[3.1.56.24]tridecan-9-yl)-6-(((6aS,8S)-8-((methoxymethoxy)methyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)methanol[39]

The title compound was synthesized by proceeding analogously asdescribed in Examples 36 and 37, from(6aS,8S)-4-iodo-8-((methoxy)meth)yl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazineand (S)-13-oxa-9-azadispiro[3.1.5⁶.2⁴]tridecan-5-amine dihydrochloride.MS (ES, m/z): [M+1]⁺=585.3.

(3-((3S,4S)-4-Amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((6aS,8S)-8-(((methoxymethoxy)methoxy)methyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)methanol[40]

was isolated as a side product.

Example 41 Synthesis of(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((6aS,8S)-8-(hydroxymethyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)methanol

Step 1:(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((6aS,8S)-8-(hydroxymethyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)methanol

During synthesis of Example 31, compound 42 was also isolated as sideproduct. MS (ES, m/z): [M+1]⁺=515.3.

Example 42 Synthesis of(3S,4S)-8-(5-(((6aS,8S)-8-((methoxymethoxy)methyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

Step 1:(6aS,8S)-4-((5-chloropyrazin-2-yl)thio)-8-((methoxymethoxy)methyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine

A mixture of(6aS,8S)-4-iodo-8-((methoxymethoxy)methyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine (90 mg, 0.239 mmol, 1.00 equiv), sodium5-chloropyrazine-2-thiolate (61 mg, 0.36 mmol, 1.51 equiv)(seeWO2016/203406), Pd₂(dba)₃ (22 mg, 0.024 mmol, 0.10 equiv), Xantphos (14mg, 0.024 mmol, 0.10 equiv) and DIEA (93 mg, 0.72 mmol, 3.0 equiv) inTHF (2 mL) was stirred for 0.5 h at 60° C. under nitrogen atmosphere.The residue was purified by silica gel column chromatography to affordthe title compound (93 mg, 98.5%) as brown oil. MS (ES, m/z):[M+1]⁺=395.2.

Step 2:(3S,4S)-8-(5-(((6aS,8S)-8-((methoxymethoxy)methyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

A solution of(6aS,8S)-4-(5-chloropyrazin-2-yl)thio)-8-((methoxymethoxy)methyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine(40 mg, 0.101 mmol, 1.00 equiv),(3S,48)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine dihydrochloride (42mg, 0.173 mmol, 1.70 equiv) and DIEA (65 mg, 0.50 mmol, 5.00 equiv) inCH₃CN (0.40 mL) was stirred for 16 h at 100° C. The residue was purifiedby Pre-HPLC to afford the title compound (16 mg, 29.9%) as off-whitesolid. MS (ES, m/z): [M+1]⁺=529.3

Example 43 Synthesis of(3S,4S)-8-(5-(((6aS,8S)-8-(methoxymethyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

The title compound was synthesized by proceeding analogously asdescribed in Example 42. MS (ES, m/z): [M+1]⁺=499.3.

Example 44 Synthesis of(3S,4S)-8-(6-amino-5-(((6aS,8S)-8-((methoxymethoxy)methyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-48-azaspiro[4.5]decan-4-amine

Step 1:6-chloro-3-(((6aS,8S)-8-((methoxymethoxy)methyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-amine

A mixture of(6aS,8S)-4-iodo-8-((methoxymethoxy)methyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine(90.00 mg, 0.239 mmol, 1.00 equiv), sodium3-amino-5-chloropyrazine-2-thiolate (60 mg, 0.359 mmol, 1.5 equiv)(seeWO2015/107494), Pd₂(dba)₃ (22 mg, 0.024 mmol, 0.1 equiv), Xantphos (14mg, 0.024 mmol, 0.1 equiv) and DIEA (93 mg, 0.72 mmol, 3.0 equiv) in THF(2.00 mL) was stirred for 0.5 h at 60° C. under nitrogen atmosphere. Theresidue was purified by silica gel column chromatography and to affordthe title compound (93 mg, 98.9%) as a brown oil.

Step 2:(3S,4S)-8-(6-amino-5-(((6aS,8S)-8-((methoxymethoxy)methyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

A solution of6-chloro-3-(((6aS,8S)-8-((methoxymethoxy)methyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-amine(40mg, 0.1 mmol, 1.00 equiv),(3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine dihydrochloride (42mg, 0.17 mmol, 1.76 equiv) and DIEA (65 mg, 0.5 mmol, 5.1 equiv) inCH₃CN (0.40 mL) was stirred for 16 h at 100° C. The residue was purifiedby Pre-HPLC to afford the title compound (16 mg, 30%) as off-whitesolid. MS (ES, m/z): [M+1]⁺=544.3.

Example 45 Synthesis of(3S,4S)-8-(6-amino-5-(((6aS,8S)-8-(methoxymethyl)-4a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-yl)thio)pyrazine-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

The title compound was synthesized by proceeding analogously asdescribed in Example 44. MS (ES, m/z): [M+1]⁺=514.3

Example 46 Synthesis of(S)-1′-(5-(((6aS,8S)-8-((methoxymethoxy)methyl)-4a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine

A solution of(6aS,8S)-4-((5-chloropyrazin-2-yl)thio)-8-((methoxymethoxy)methyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine(40 mg, 0.10 mmol, 1.0 equiv),(S)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-aminetrihydrochloride (48 mg, 0.15 mmol, 1.5 equiv) and DIEA (65 mg, 0.50mmol, 5.00 equiv) in CH₃CN (0.40 mL) was stirred for 16 h at 100° C. Thereaction solution was purified by Pre-HPLC to afford the title compound(12.0 mg, 21.2%) as off-white solid, MS (ES, m/z): [M+1]⁺=562.3.

Example 47 Synthesis of(S)-1′-(6-amino-5-(((6aS,8S)-8-((methoxymethoxy)methyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine

A solution of6-chloro-3-(((6aS,8S)-8-((methoxymethoxy)methyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-amine(40 mg, 0.098 mmd, 1.00 equiv),(S)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-aminetrihydrochloride (46 mg, 0.147 mmol, 1.50 equiv) and DIEA (63 mg, 0.487mmd, 5.0 equiv) in CH₃CN (0.40 mL) was stirred for 16 h at 100° C. Thereaction solution was purified by Pre-HPLC to afford the title compound(16.0 mg, 28.4%) as an off-white solid. MS (ES, m/z): [M+1]⁺=5773.

Example 48 Synthesis of(3-((S)-5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)-6-(((6aS,8S)-8-((methoxymethoxy)methyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo-[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)methanol

To a stirred solution of(S)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-aminetrihydrochloride (28 mg, 0.09 mmol, 1.53 equiv) and DIEA (38 mg, 0.294mmol, 5.0 equiv) in ACN (0.5 mL) was added(3-chloro-6-(((6aS,8S)-8-((methoxymethoxy)methyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)methanol(25 mg, 0.059 mmol, 1.00 equiv) at room temperature under nitrogenatmosphere. The resulting mixture was stirred overnight at 100° C. andthe mixture was allowed to cool down to room temperature. The crudeproduct was purified by Prep-HPLC to afford the title compound (6.5 mg,18.67%) as a white solid. MS (ES, m/z): [M+1]⁺=592.3.

Example 49 Synthesis of(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((6aS,8S)-8-((methoxymethoxy)methyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)-5-methylpyrazin-2-yl)methanol

The title compound was synthesized by proceeding analogously asdescribed in Example 31. MS (ES, m/z): [M+1]⁺=573.3.

Example 50 Synthesis of(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((6aS,8R)-8-((methoxymethoxy)methyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)methanol

Step 1:(3-chloro-6-(((6aS)-8-((methoxymethoxy)methyl)-6a,7,8,9-tetrahydro-6H-pyrido-[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)methanol

Into a mixture of(6aS)-4-iodo-8-((methoxymethoxy)methyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine(1.00 g, 2.658 mmol, 1.00 equiv) and sodium5-chloro-6-(hydroxymethyl)pyrazine-2-thiolate (0.78 g, 3.93 mmol, 1.48equiv) in THF (10.00 mL) were added XantPhos (0.15 g, 0.26 mmol, 0.10equiv) and DIEA (1.02 g, 7.892 mmol, 2.97 equiv) at room temperature.Pd₂(dba)₃ (0.12 g, 0.13 mmol, 0.05 equiv) was then added to the solutionunder nitrogen atmosphere and the resulting mixture was stirred for 1 hat 60° C. under nitrogen atmosphere. The resulting mixture was cooled tort and filtered and the filtrate was concentrated under reduced pressureand the residue was purified by silica gel column chromatography, elutedwith PE/EA (0˜100%) to afford product (790 mg, 69.9%).

Step 2:(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((6aS,8R)-8-((methoxymethoxy)methyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)methanol

Into a mixture of (3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-aminedihydrochloride (730 mg, 3.002 mmol, 1.72 equiv) and DIEA (1.30 g, 10.06mmol, 5.77 equiv) in ACN (5 mL) was added(3-chloro-6-(((6aS)-8-((methoxymethoxy)methyl)-4a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)methanol (740 mg, 1.742 mmol, 1.00 equiv) at roomtemperature. The resulting mixture was stirred for 16 h at 60° C. undernitrogen atmosphere and then purified by Prep-HPLC and chiral HPLC toafford product. MS (ES, m/z): [M+1]⁺=559.3.

Example 51 and 52 Synthesis of(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((6aR,8S)-8-((methoxymethoxy)methyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)methanoland(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((6aR,8R)-8-((methoxymethoxy)methyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)methanol

Step 1:(6aR)-4-iodo-8-((methoxymethoxy)methyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine

The title compound was synthesized by proceeding analogously asdescribed in Examples 29-30, steps 1-6.

Step 2:(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((6aR,8S)-8-((methoxymethoxy)methyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)methanoland(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro-[4.5]decan-8-yl)-6-(((6aR,8R)-8-((methoxymethoxy)methyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)methanol

A mixtures of title compounds was synthesized by proceeding analogouslyas described in Example 31, steps 5-8. The material was then purified byHPLC to give compounds 51 and 52. Compound 51: MS (ES, m/z):[M+1]⁺=559.3. Compound 52: MS (ES, m/z): [M+1]=559.3.

Example 53 Synthesis of(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-((6aS,8S)-8-(methoxymethyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)pyrazin-2-yl)methanol

Step 1:((6aS,8S)-8-(methoxymethyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d]-[1,4]oxazin-4-yl)boronicacid

To a stirred solution of(6aS,8S)-4-iodo-8-(methoxymethyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine(100 mg, 0.289 mmol, 1.00 equiv),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (110 mg,0.433 mmol, 1.5 equiv), AcOK (57 mg, 0.581 mmol, 2.0 equiv) in toluene(2 mL) was added Pd(dppf)Cl₂ (12 mg, 0.0164 mmol, 0.057 equiv) at roomtemperature under N2 atmosphere. The resulting mixture was stirred for16 h at 100° C. under N2 atmosphere and the resulting mixture was useddirectly in next step without further purification.

Step 2: tert-butyl((3S,4S)-8(3-(hydroxymethyl)-5-((6aS,8S)-8-(methoxymethyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate

To the mixture of((6aS,8S)-8-(methoxymethyl)-6a,7,8,9-tetrahydro-6H-pyrid[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)boronicacid in toluene from last step were added K₂CO₃(120 mg, 0.87 mmol, 3.00equiv), tert-butyl((3S,4S)-8-(5-bromo-3-(hydroxymethyl)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate(132 mg, 0.290 mmol, 1.00 equiv), Pd(dppf)Cl₂ (12.00 mg, 0.064 mmol,0.057 equiv) and H₂O (0.2 mL) under N2. After stirring for 3 h at 100°C., the resulting mixture was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography, eluted withEA, to afford the title compound (70 mg, 40.7%, 2 steps) as alight-yellow oil. MS (ES, m/z): [M+1]=597.3.

Step 3:(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-64(6aS,8S)-8-(methoxymethyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)pyrazin-2-yl)methanol

A mixture of tert-butyl((3S,4S)-8-(3-(hydroxymethyl)-5-((6aS,8S)-8-(methoxymethyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate(70 mg, 0.117 mmol, 1.00 equiv) in DCM (3 mL) and TFA (1 mL) was stirredat room temperature for 3 h. The resulting mixture was concentrated andpurified by Prep-HPLC to afford the title compound (17 mg, 29.3%). MS(ES, m/z): [M+H]⁺=497.3.

Example 54 Synthesis of(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-((6aS,8S)-8-((methoxymethoxy)methyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)pyrazin-2-yl)methanol

The title compound was synthesized by proceeding analogously asdescribed in Example 54. MS (ES, m/z): [M+H]⁺=527.3.

Biological Assays SHP2 Allosteric Inhibition Assay

SHP2 possesses two N-terminal Src homology 2 (SH2) domains, a centralprotein-tyrosine phosphatase (PTP) domain, and C-terminal tail. At thebasal state, SHP2 is auto-inhibited and access of substrates to thecatalytic site is blocked by the intermolecular interactions between theSH2 domains and the PTP domain. When bis-tyrosyl-phosphorylated peptidesbind to SH2 domain of SHP2, the PTP domain becomes available forsubstrate recognition and reaction catalysis and SHP2 is allostericallyactivated. SHP2 catalytic activity can be measured using a fluorogenicartificial substrate DiFMUP.

The phosphatase reactions were carried out at room temperature in384-well black polystyrene plates (Greiner Bio-One, Cat #784076) usingassay buffers containing 60 mM HEPES, pH 7.2, 75 mM NaCl, 75 mM KCl, 1mM EDTA, 0.05% P-20, and 5 mM DTT.

0.33 nM of SHP2 was co-incubated with of 0.5 μM of bisphos-IRS1 peptide(sequence: H2N-LN(pY)IDLDLV(dPEG8)IST(pY)ASINFQK-amide) and variousconcentrations of compounds for 30-60 min at room temperature. Then thereaction was initiated by addition of the surrogate substrate DiFMUP(Invitrogen, Cat #D6567, 100 uM final).

The real-time conversion of DiFMUP to DiFMU (6,8-difluoro-7-hydroxyl-4-methyl-coumarin) was measured every 5 min for 30min using a microplate reader (CLARIOstar, BMG Labtech) with excitationand emission wavelengths of 340 nm and 450 nm, respectively. Initialreaction rates were determined by linear fitting of the data and theinhibitor dose response curves were analyzed using normalized IC₅₀regression curve fitting with control-based normalization.

The IC₅₀ value for compounds as numbered in compound Table 1 above areprovided below in Table 4 below, where the IC₅₀ was measured as 100 nMor less.

TABLE 4 Compound Shp2 # from Table 1 Structure IC₅₀(nM) 1

3 2

4 3

13 4

5 5

8 6

6 7

6 8

8 9

8 10

10 11

14 12

12 13

8 14

5 15

10 16

3 17

2 18

one of 21 and 22 is 13 and the other is 8 19

20

11 21

13 22

6 23

8 24

10 25

11 26 and 27

one of 26 and 27 is 10 and the other is 8

28

13 29

3.6 30

3.8 31

4.2 32

4 33

2.3 34

6.2 35

18 36 and 37

One of 36 and 37 is 2.7 and the other is 4.2

38

5.7 39

7.0 40

5.9 41

5.0 42

5.9 43

4.5 44

5.9 45

9.4 46

3.9 47

8.4 48

3.3 49

12 50

3.5 51

4.9 52

3.7

p-ERK Cellular Amy

Detroit562 cells were seeded in 96-well plate and cultured overnight(30,000 cells per well, 200 ul total volume). Following morning, cellswere treated with compounds of the disclosure, with startingconcentration at 10 uM and ½ log dilution down to 1 nM for 2 hours at37° C. DMSO treatment serves as control. p-ERK was then measured usingAlphaUSA® SureFire® Ultra™ p-ERK 1/2 (Thr202/Tyr204) Assay Kit(PerkinElmer, ALSU-PERK-A500) following instruction. Briefly, medium wasremoved and add 50 ul 1× lysis buffer was added, followed by 10 minutesincubation on a plate shaker at room temperature. Then 10 ul of lysatewas transferred to a white 384-well plate, and 5 ul Acceptor mix, and 5ul Donor mix were added (both prepared according to manufacturer'sinstruction). The plate was wrapped with foil, shaken for 1-2 minutes ona plate reader and incubated for >2 hours, Signal was then measured on aCLARIOstar® plate reader. Percentage inhibition was calculated with DMSOtreatment as 100% of signal, and IC₅₀ is calculated by Graphpad Prism 7.

FORMULATION EXAMPLES

The following are representative pharmaceutical formulations containinga compound of Formula (I).

Tablet Formulation

The following ingredients are mixed intimately and pressed into singlescored tablets.

Quantity per Ingredient tablet (mg) Compound of the disclosure 400cornstarch  50 croscarmellose sodium  25 lactose 120 magnesium stearate 5

Capsule Formulation

The following ingredients are mixed intimately and loaded into ahard-shell gelatin capsule.

Quantity per Ingredient tablet (mg) Compound of the disclosure 200lactose spray dried 148 magnesium stearate  2

Injectable Formulation

Compound of the disclosure (e.g., compound 1) in 2% HPMC, 1% Tween 80 inDI water, pH 2.2 with MSA, q.s. to at least 20 mg/mL

Inhalation Composition

To prepare a pharmaceutical composition for inhalation delivery, 20 mgof a compound disclosed herein is mixed with 50 mg of anhydrous citricacid and 100 mL of 0.9% sodium chloride solution. The mixture isincorporated into an inhalation delivery unit, such as a nebulizer,which is suitable for inhalation administration.

Topical Gel Composition

To prepare a pharmaceutical topical gel composition, 100 mg of acompound disclosed herein is mixed with 1.75 g of hydroxypropylcellulose, 10 mL of propylene glycol, 10 mL of isopropyl myristate and100 mL of purified alcohol USP. The resulting gel mixture is thenincorporated into containers, such as tubes, which are suitable fortopical administration.

Ophthalmic Solution Composition

To prepare a pharmaceutical ophthalmic solution composition, 100 mg of acompound disclosed herein is mixed with 0.9 g of NaCl in 100 mL ofpurified water and filtered using a 0.2 micron filter. The resultingisotonic solution is then incorporated into ophthalmic delivery units,such as eye drop containers, which are suitable for ophthalmicadministration.

Nasal Spray Solution

To prepare a pharmaceutical nasal spray solution, 10 g of a compounddisclosed herein is mixed with 30 mL of a 0.05M phosphate buffersolution (pH 4.4). The solution is placed in a nasal administratordesigned to deliver 100 ul of spray for each application.

What is claimed:
 1. A method of making a compound of Formula (IC):

wherein: A and E are independently selected from a bond, CH₂, O, NH, S,and S(O)₂; Z is hydrogen, alkyl, alkoxy, alkoxymethyl,methoxyalkoxymethyl, hydroxymethyl, halo, haloalkyl, haloalkoxy, cyano,cycloalkyl, heterocyclyl, heteroaryl(wherein cycloalkyl, heterocyclyl,and heteroaryl are optionally substituted with one to three halo),—O(alk)_(y)R^(a), —O(alk)OR^(b), —S(O)R^(c), —S(O)₂R^(d),—NR^(e)C(O)R^(f), —NR^(g)SO₂R^(h), —OC(O)NR^(i)R^(j), —C(O)NR^(k)R^(m),—S(O)₂NR^(n)R^(o), —NR^(p)R^(q), —NR^(r)C(O)C(O)R^(s) or -Y-M (wherein Yis bond, O, or SO₂ and M is alkyl, haloalkyl, cycloalkyl, heterocyclyl,or heteroaryl wherein alkyl, haloalkyl, cycloalkyl, heterocyclyl andheteroaryl are substituted with —O(alk)_(y)R^(a), —O(alk)OR^(b),—S(O)R^(c), —S(O)R^(d), —NR^(e)C(O)R^(f), —NR^(g)SO₂R^(h),—OC(O)NR^(i)R^(j), —C(O)NR^(k)R^(m), —S(O)₂NR^(n)R^(o), —NR^(p)R^(q), or—NR^(r)C(O)C(O)R^(s) and cycloalkyl, heterocyclyl, and heteroaryl areoptionally further substituted with 1 to 3 halo); wherein each y is 0 or1, each alk is alkylene, and each R^(c), R^(d), R^(f), R^(h), and R^(s)are independently alkyl, cycloalkyl, cycloalkylalkyl, optionallysubstituted heterocyclyl, optionally substituted heterocyclylalkyl,optionally substituted aryl, optionally substituted aralkyl, optionallysubstituted heteroaryl, or optionally substituted heteroaralkyl; andeach R^(a), R^(b), R^(e), R^(g), R^(i), R^(j), R^(k), R^(m), R^(n),R^(o), R^(p), R^(q), R^(r), and R^(s) are independently hydrogen, alkyl,cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted heteroaryl, or optionally substitutedheteroaralkyl; or, independently of each other, each R^(i) and R^(j),R^(k) and R^(m), R^(n) and R^(o), and R^(p) and R^(q), together with thenitrogen atom to which they are attached form optionally substitutedheterocyclyl; R₁, R², R³, and R⁴ are independently selected fromhydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, cyano,hydroxy, hydroxylalkyl, amino, and aminoalkyl; or one of R¹ and R², andR³ and R⁴, when attached to the same carbon, combine to form oxo,alkyldienyl, 3 to 6 membered cycloalkylene, or 4 to 6 memberedoptionally substituted heterocyclylene; R⁵ and R⁶ are independentlyselected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy,alkoxy, hydroxy, cyano, hydroxylalkyl, amino, and aminoalkyl, or whereinone of R⁵ and R⁶ is optionally substituted heterocyclyl and the other isselected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy,alkoxy, hydroxy, cyano, hydroxylalkyl, amino, and aminoalkyl; L is bond,O, S, S(O), S(O)₂, or CR⁷R⁸ where R⁷ and R⁸ are independently hydrogenor alkyl; Z¹ is a group of formula (a):

wherein: R⁹ is hydrogen, alkyl, halo, hydroxy, amino, or haloalkyl; R¹⁰is hydrogen, alkyl, halo, hydroxy, hydroxyalkyl, —CD₂OH, alkylsulfoxide,alkylsulfonyl, amino, aminoalkyl, aminosulfonyl, aminocarbonyl, carboxy,cyano, or alkoxycarbonyl; R¹³ is hydrogen, alkyl, halo, hydroxy, amino,or haloalkyl; R¹⁴ is hydrogen, alkyl, or haloalkyl; R¹¹ and R¹⁵ areselected from amino and aminoalkyl; R¹² and R¹⁶ are selected fromhydrogen, cyano, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl,aryl, heterocyclyl, and heteroaryl, where alkyl, cycloalkyl, aryl,heterocyclyl and heteroaryl are optionally substituted with one to threesubstituents independently selected from alkyl, halo, haloalkyl,haloalkoxy, alkoxy, and cyano; or R¹¹ and R¹², and R¹⁵ and R¹⁶ togetherwith the carbon atom to which they are attached form a ring of formula(c):

wherein: e is 0, 1, or 2; k is 0, 1, or 2 provided e+k is 1, 2, or 3; qis 0, 1, or 2, or 3; R¹⁷ and R¹⁸ are independently selected fromhydrogen, alkyl, cycloalkyl, and haloalkyl; each R¹⁹ is independentlyselected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy,hydroxy, cyano, alkylsulfoxide, alkylsulfonyl, oxo, cycloalkyl,optionally substituted heterocyclyl, and optionally substitutedheteroaryl; or when two R¹⁹ groups are attached to the same carbon atom,the two R¹⁹ groups together with the carbon atom to which they areattached form cycloalkylene or heterocyclylene. ring D is absent orpresent; wherein: (i) when ring D is absent, then one of Q and W is CH₂,O, S, S(O), S(O)₂, or NH; and the other of Q and W is CH₂; and (ii) whenring D is present, then Q and W are independently N or C provided onlyone of Q and W is N; and ring D is phenyl or a 5 or 6 memberedheteroaryl ring which, including Q and W, contains one to threeheteroatoms independently selected from N, O, and S and ring D isoptionally substituted with one or two substituents independentlyselected from alkyl, cycloalkyl, halo, haloalkyl, alkoxy, haloalkoxy,hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, carboxy, and optionallysubstituted heterocyclyl; or a pharmaceutically acceptable salt thereof;the method comprising: reacting a compound of Formula 1-a or 1-c:

with a compound of Formula 1-d or 1-e, respectively:

wherein X¹ is halogen; and M is a metal.
 2. The method of claim 1,wherein the reacting step is transition metal-catalyzed.
 3. The methodof claim 2, wherein the transition metal comprises palladium.
 4. Themethod of claim 3, wherein reacting step further comprises bidentatephosphine.
 5. The method of claim 4, wherein the bidentate phosphine isxantphos.
 6. The method of claim 1, wherein the metal is potassium orsodium.
 7. The method of claim 1, wherein X¹ is bromine or iodine. 8.The method of claim 1, wherein the compound of Formula (IC) is selectedfrom the group consisting of:


9. The method of 1, wherein the compound of Formula (IC) is selectedfrom the group consisting of:


10. The method of claim 1, wherein the compound of Formula 1-a is((6aS,8S) 4-iodo-6a,7,8,9-tetrahydro-6R-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-8-yl)methanol:


11. The method of claim 1, wherein the compound of Formula 1-a is(6aS,8S)-4-iodo-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-8-ol:


12. A compound of Formula (I):

wherein: A and E are independently selected from a bond, CH₂, O, NH, S,and S(O)₂; Z is hydrogen, alkyl, halo, haloalkyl, haloalkoxy, cyano,cycloalkyl, heterocyclyl, heteroaryl (wherein cycloalkyl, heterocyclyl,and heteroaryl are optionally substituted with one to three halo),—O(alk)_(y)R^(a), —O(alk)OR^(b), —S(O)R^(c), —S(O)₂R^(d),—NR^(e)C(O)R^(f), —NR^(g)SO₂R^(h), —OC(O)NR^(i)R^(j), —C(O)NR^(k)R^(m),—S(O)₂NR^(n)R^(o), —NR^(p)R^(q), —NR^(r)C(O)C(O)R^(s) or -Y-M (wherein Yis bond, O, or SO₂ and M is alkyl, haloalkyl, cycloalkyl, heterocyclyl,or heteroaryl wherein alkyl, haloalkyl, cycloalkyl, heterocyclyl andheteroaryl are substituted with —O(alk)_(y)R, —O(alk)OR^(b), —S(O)R^(c),—S(O) R^(d), —NR^(e)C(O)R^(f), —NR^(g)SO₂R^(h), —OC(O)NR^(i)R^(j),—C(O)NR^(k)R^(m), —S(O)₂NR^(n)R^(o), —NR^(p)R^(q), or—NR^(r)C(O)C(O)R^(s) and cycloalkyl, heterocyclyl, and heteroaryl areoptionally further substituted with 1 to 3 halo); wherein each y is 0 or1, each alk is alkylene, and each R^(c), R^(d), R^(f), R^(h), and R^(s)are independently alkyl, cycloalkyl, cycloalkylalkyl, optionallysubstituted heterocyclyl, optionally substituted heterocyclylalkyl,optionally substituted aryl, optionally substituted aralkyl, optionallysubstituted heteroaryl, or optionally substituted heteroaralkyl; andeach R^(a), R^(b), R^(e), R^(g), R^(i), R^(j), R^(k), R^(m), R^(n),R^(o), R^(p), R^(q), R^(r), and R^(s) are independently hydrogen, alkyl,cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted heteroaryl, or optionally substitutedheteroaralkyl; or, independently of each other, each R^(i) and R^(j),R^(k) and R^(m), R^(n) and R^(o), and R^(p) and R^(q), together with thenitrogen atom to which they are attached form optionally substitutedheterocyclyl; R¹, R², R³, and R⁴ are independently selected fromhydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, cyano,hydroxy, hydroxylalkyl, amino, and aminoalkyl; or one of R¹ and R² andR³ and R⁴, when attached to the same carbon, combine to form oxo,alkyldienyl, 3 to 6 membered cycloalkylene, or 4 to 6 memberedoptionally substituted heterocyclylene; R⁵ and R⁶ are independentlyselected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy,alkoxy, hydroxy, cyano, hydroxylalkyl, amino, and aminoalkyl, or whereinone of R⁵ and R⁶ is optionally substituted heterocyclyl and the other R⁵and R⁶ is selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl,haloalkoxy, alkoxy, hydroxy, cyano, hydroxylalkyl, amino, andaminoalkyl; L is bond, O, S, S(O), S(O)₂, or CR⁷R⁸ where R⁷ and R⁸ areindependently hydrogen or alkyl; Z¹ is a group of formula (a) or (b):

wherein: R⁹ is hydrogen, alkyl, halo, hydroxy, amino, or haloalkyl; R¹⁰is hydrogen, alkyl, halo, hydroxy, hydroxyalkyl, —CD2OH, alkylsulfoxide,alkylsulfonyl, amino, aminoalkyl, aminosulfonyl, aminocarbonyl, carboxy,cyano, or alkoxycarbonyl; R¹³ is hydrogen, alkyl, halo, hydroxy, amino,or haloalkyl; R¹⁴ is hydrogen, alkyl, or haloalkyl; R¹¹ and R¹⁵ areselected from amino and aminoalkyl; R¹² and R¹⁶ are selected fromhydrogen, cyano, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl,aryl, heterocyclyl, and heteroaryl, where alkyl, cycloalkyl, aryl,heterocyclyl and heteroaryl are optionally substituted with one to threesubstituents independently selected from alkyl, halo, haloalkyl,haloalkoxy, alkoxy, and cyano; or R¹¹ and R¹², and R¹⁵ and R¹⁶ togetherwith the carbon atom to which they are attached form a ring of formula(c):

wherein: e is 0, 1, or 2; k is 0, 1, or 2 provided e+k is 1, 2, or 3; qis 0, 1, or 2, or 3; R¹⁷ and R¹⁸ are independently selected fromhydrogen, alkyl, cycloalkyl and haloalkyl; each R¹⁹ is independentlyselected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy,hydroxy, cyano, alkylsulfoxide, alkylsulfonyl, oxo, cycloalkyl,optionally substituted heterocyclyl, and optionally substitutedheteroaryl; or when two R¹⁹ groups are attached to the same carbon atom,the two R¹⁹ groups together with the carbon atom to which they areattached form cycloalkylene or heterocyclylene. ring D is absent orpresent; wherein: (i) when ring D is absent, then one of Q and W is CH₂,O, S, S(O), S(O)₂, or NH; and the other of Q and W is CH₂; and (ii) whenring D is present, then Q and W are independently N or C provided onlyone of Q and W is N; and ring D is phenyl or a 5 or 6 memberedheteroaryl ring which, including Q and W, contains one to threeheteroatoms independently selected from N, O, and S and ring D isoptionally be substituted with one or two substituents independentlyselected from alkyl, cycloalkyl, halo, haloalkyl, alkoxy, haloalkoxy,hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, carboxy, and optionallysubstituted heterocyclyl; or a pharmaceutically acceptable salt thereof.13. The compound of claim 12, or a pharmaceutically acceptable saltthereof wherein Z is -Y-M (wherein Y is bond and M is alkyl, haloalkyl,cycloalkyl, heterocyclyl, or heteroaryl wherein alkyl, haloalkyl,cycloalkyl, heterocyclyl and heteroaryl are substituted with—O(alk)OR^(a) where R^(a) is alkyl, cycloalkyl, cycloalkylalkyl,aminoalkyl, optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted aryl, or optionallysubstituted heteroaryl.
 14. The compound of claim 12, or apharmaceutically acceptable salt thereof wherein Z is -Y-M (wherein Y isbond or O and M is alkyl, haloalkyl, cycloalkyl, heterocyclyl, orheteroaryl wherein alkyl, haloalkyl, cycloalkyl, heterocyclyl andheteroaryl are substituted with —O(alk)OR^(b), —S(O)₂R^(d),—NR^(e)C(O)R^(f), —NRgSO₂R^(h), —OC(O)NRiRj, —C(O)NR^(k)R^(m), or—S(O)₂NR^(n)R^(o).
 15. The compound of claim 12, or a pharmaceuticallyacceptable salt thereof wherein Z is -Y-M (wherein Y is bond and M isalkyl, haloalkyl, cycloalkyl, heterocyclyl, or heteroaryl wherein alkyl,haloalkyl, cycloalkyl, heterocyclyl and heteroaryl are substituted with—O—R^(a) where R^(a) is alkyl, cycloalkyl, cycloalkylalkyl, aminoalkyl,optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted aryl, or optionallysubstituted heteroaryl.
 16. The compound of claim 12, or apharmaceutically acceptable salt thereof wherein Z is —OR^(a) whereR^(a) is alkyl, cycloalkyl, cycloalkylalkyl, aminoalkyl, optionallysubstituted heterocyclyl, optionally substituted heterocyclylalkyl,optionally substituted aryl, or optionally substituted heteroaryl. 17.The compound of claim 12, or a pharmaceutically acceptable salt thereofwherein Z is —O(alk)OR^(b) where R^(b) is alkyl, cycloalkyl,cycloalkylalkyl, aminoalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substituted aryl,or optionally substituted heteroaryl.
 18. The compound of claim 12, or apharmaceutically acceptable salt thereof wherein Z is hydrogen, alkyl,halo, haloalkyl, haloalkoxy, cyano, cycloalkyl, heterocyclyl, heteroaryl(wherein cycloalkyl, heterocyclyl, and heteroaryl are optionallysubstituted with one to three halo), —O(alk)_(y)R^(a), —O(alk)OR^(b),—S(O)₂R^(d), —OC(O)NRiRj, —S(O)₂NR^(n)R^(o), —NR^(p)R^(q), or -Y-M(wherein Y is bond, O, or SO₂ and M is alkyl, haloalkyl, cycloalkyl,heterocyclyl, or heteroaryl wherein alkyl, haloalkyl, cycloalkyl,heterocyclyl and heteroaryl are substituted with—O(alk)_(y)R^(a),—O(alk)OR^(b), —S(O)₂R^(d), or —NR^(p)R^(q) andcycloalkyl, heterocyclyl, and heteroaryl are optionally furthersubstituted with 1 to 3 halo).
 19. The compound of claim 13, or apharmaceutically acceptable salt thereof wherein Z ismethoxymethyloxymethyl, ethoxymethyloxymethyl, methoxyethyloxymethyl,cyclopropylmethyloxymethyl, or oxetan-3-ylmethyloxymethyl.
 20. Thecompound of claim 13, or a pharmaceutically acceptable salt thereofwherein Z is methoxymethyloxy, methoxyethyloxy, methoxymethyl,methoxymethyloxymethyl, ethoxymethyloxymethyl, methoxyethyloxymethyl,cyclopropylmethyloxy, or oxetan-3-ylmethyloxymethyl.
 21. The compound ofclaim 13, or a pharmaceutically acceptable salt thereof wherein Z ishydrogen, fluoro, cyano, methoxy, hydroxy, cyclopentyloxy,tetrahydrofuran-3-yloxy, oxetan-3-yloxy, methoxymethyloxy,methoxyethyloxy, methylsulfonyl, aminocarbonyloxy, pyrazol-1-yl,hydroxymethyl, methoxymethyl, ethoxymethyl, methoxymethyloxymethyl,ethoxymethyloxymethyl, methoxyethyloxymethyl, cyclopropylmethyloxy, oroxetan-3-ylmethyloxymethyl.
 22. The compound of claim 13, or apharmaceutically acceptable salt thereof wherein Z is fluoro.
 23. Thecompound of any one of claims 12-22, or a pharmaceutically acceptablesalt thereof is wherein the compound has a structure of formula (II):


24. The compound of any one of claims 12-22, and or a pharmaceuticallyacceptable salt thereof is wherein the compound has a structure ofFormula (HA):


25. The compound of any one of claims 12-22, or a pharmaceuticallyacceptable salt thereof is wherein the compound has a structure offormula (I):


26. The compound of any one of claims 12-22, or a pharmaceuticallyacceptable salt thereof is wherein the compound has structure of Formula(IIA):


27. A method of treating a disease treatable by inhibition of SHP2 in apatient which method comprises administering to the patient, in need ofsuch treatment, a therapeutically effective amount of a compound, orpharmaceutically acceptable salt thereof, of any one of claims 12-26.28. The method of claim 27, wherein the disease is cancer.
 29. Themethod of claim 28, wherein the cancer is selected from lung cancer,stomach cancer, liver cancer, colon cancer, kidney cancer, breastcancer, pancreatic cancer, juvenile myelomonocytic leukemia,neuroblastoma, melanoma, and acute myeloid leukemia.